Obesity starts in the brain


Where does obesity begin?  What drives you to eat too much or expend too little energy, and why has there been such a dramatic increase in obesity since 1980? Some recently popular explanations are the carbohydrate / insulin hypothesis (CIH), singling out the prevalence of carbohydrates in the diet, and the food reward hypothesis (FRH), putting the primary blame on the availability of “hyper-palatable” food.

In this post I will present evidence for new paradigm, which I call the  Hypothalamic Hypothesis (HH).  I think it provides a better explanation for the facts of obesity than the CIH and FRH theories, and leads to some different advice about how best to lose weight.

Some recent research suggests that obesity starts with specific physical changes to the brain. Appetite is regulated by the hypothalamus, particularly the arcuate nucleus (ARC), ventromedial hypothalamus (VMH) and lateral hypothalamus (LH). It turns out that two very specific changes to the brain cause us to get get hungry, overeat, burn less fat, and gain weight. And these changes to particular brain structures come about as a result of what you eat, eating frequency, and to some extent your activity level. The problem of obesity or overweight is often portrayed as a single problem, but it is really two problems, and each type of obesity corresponds to one type of brain alteration. Failure to distinguish these two types of obesity has resulted in much confusion. In part, the confusion comes about because these two types of obesity frequently occur together in the same individual, although one type is usually dominant. If you understand this, and you understand the role your brain plays, you can become more successful at losing excess weight.

I’ll spend a little time explaining the theory, provide some specific suggestions for how it can help you fine tune your weight loss program, and try to point out why I think the Hypothalamic Hypothesis overcomes some weaknesses of the other obesity theories.



Two types of obesity.  One major type of obesity is subcutaneous (SC) obesity.  The man on the right is a Sumo wrestler with subcutaneous obesity,  but you don’t have to be a wrestler to have this type of fat distribution.  It is characterized by lots of looser, softer fat hanging from the torso, arms, legs and even the face.  A double chin and skin folds under the arms are not uncommon for this type.  SC obesity is more common among women than men.

The second major type of obesity is visceral or “intra-abdominal” (IA) obesity. This is depicted by the classic “beer belly” sported by the main in the left photograph, characterized by a protuberant gut, but frequently not a lot of extra fat on the legs or arms. It’s quite prevalent among men, but seen on many women as well.

The above photos show extreme types, but it is common for both types of obesity to coexist in the same person, in varying degrees.  Those with predominant IA obesity are sometimes referred to as “apples”; those with predominant SC obesity are called “pears”.


Different metabolisms. The difference between subcutaneous and intra-abdominal obesity is not merely a matter of how adipose tissue is distributed on the body, but also about the biological composition of the fat tissue and it’s metabolic activity.  Subcutaneous fat is located just beneath the skin, and on the outside of the muscle tissue, all over the body.  By contrast, intra-abdominal fat– also called visceral fat–is located underneath the visceral muscles, deep within the gut.  It  surrounds the digestive organs — the liver, pancreas, stomach and intestines.  The difference can be seen clearly in the CT scans at the left.  The top image shows a cross-section at mid-belly level of someone with SC obesity, with most of the dark gray fat mass located right under the skin but outside the lighter grey visceral muscles and internal organs.  The bottom image is a similar CT scan of someone with IA obesity, showing much less subcutaneous fat, but considerable fat beneath the walls of the viscera, packed around the intestines.

What is important to realize is that the adipose tissue stored inside the abdomen is biochemically and metabolically very different than the fat stored right under the skin.  Both are called “fat” or “adipose tissue” but they behave as if they were entirely different substances. The image below at left is a micrograph of SC fat; the image at right shows IA fat cells.  Notice the different shape and size, but also the substantial dark “mortar” between the IA fat cell “bricks”.





The adipose tissue in IA fat is not an inert storage tissue.  On the contrary, it is a metabolically active hormonal “organ”: it is infiltrated by macrophages and secretes “adipokines” like interleukin-6, tumor necrosis factor alpha, and C-reactive protein.  These compounds are inflammatory signaling agents, associated with insulin resistance, diabetes, hypertension, and cardiovascular disease characteristic of Metabolic Syndrome.  The health effects of this inflammatory process have been the subject of intense study.  In this article, however, I’ll address only the role that these inflammatory processes have in the development of obesity.

The appetite center.  To understand the dynamics of each type of obesity, it is important to understand how appetite and body fat are governed by the brain. The hypothalamus regulates biological drives, including feeding, sleep and hunger.  As shown in the diagram at right (and also in this video) appetite, feeding behavior and metabolic rate are regulated by two sets of neurons that have opposite effects on appetite and metabolism:

  • The  “anorexigenic” POMC/CART neurons that inhibit appetite and increase the rate of fat oxidation in the body.  In response to nutrients and certain hormones, these neurons produce the appetite-suppressing neuropeptides propio-melanocortin, cocaine-and-amphetamine-regulated transcript and α-melanocyte stimulating hormone (α-MSH). The α-MSH binds to and activates secondary melanocortin-4 (MC-4) neurons in the ventromedial hypothalamus (VHM), causing satiety and increasing energy expenditure and  fat oxidation in the body. Animals with damaged or lesioned POMC/CART neurons eat voraciously and become obese.  Both leptin and insulin are potent hormonal stimulators of the POMC/CART neurons.  These neurons have receptors for appetite suppressing signals like insulin and leptin; low levels of either hormone will increase appetite and reduce metabolic rate. If  a deficiency of leptin or insulin persists, it will lead to obesity.
  • The  “orexigenic” NPY/AgRP neurons that stimulate appetite and slow down fat oxidation in the body.  These neurons produce two neuropeptides — neuropeptide Y (NPY) and agouti-related protein (AgRP) which act to inhibit α-MSH from binding to and activating the MC-4 satiety neurons and stimulates melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH). This inhibition of MC-4 and stimulation of MCH enhances appetite and decreases metabolism and energy expenditure, conserving fat.  Animals in which the NPY/AgRP neurons have been damaged or destroyed by lesions become anorexic and lose weight.  Insulin and leptin inhibit the NPY/AgRP neurons, whereas the “meal timing” hormone ghrelin, which cyclically ebbs and flows, stimulates them.

These two sets of neurons govern fat gain and fat loss.  They effectively sense the energy status of body by centrally integrating inputs from a large number of circulating nutrients, neuropeptides and hormones, and they respond by outputting neuropeptides that drive behavior and peripheral metabolism. When they are in balance, a normal and healthful level of body fat is maintained, but when the balance of  orexigenic or anorexigenic signals shift, this adjusts the body’s fat and activity set points up or down.  As a prime example, if leptin levels in the hypothalamus are low, either because of low body weight or because the leptin is blocked from reaching its receptors in the POMC neurons, appetite will increase, fat oxidation will decrease, and this will lead to an increase in adiposity.

Insulin, leptin and appetite. There are two hormones which predominantly regulate body fat:  insulin and leptin. In healthy individuals, as Byron Richards describes,

Leptin uses adrenaline as a communication signal to fat cells, telling them to release stored fat to be used for fuel. This takes place in the course of a normal day between meals and at night during sleep…A drop in leptin signals hunger. Food intake stimulates insulin release. As a person eats, insulin is always directing some amount of triglycerides to go over to white adipose tissue and enter fat cells….This turns on the production of leptin in fat cells, causing the blood level to rise in response to the meal. As the leptin levels rise high enough, they signal to the brain that enough has been eaten. Leptin now signals the pancreas to stop making insulin…In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin and leptin resistance mean that the hormones don’t communicate efficiently in response to food.” (The Leptin Diet, p. 13, 17, 23, 36)

Increased basal levels of either of these two hormones indicates increased energy stores and adiposity. The hormones have different metabolic effects depending on their site of action.  As Lustig explains, the action of these hormones “centrally” — inside the brain — is entirely different than that in the “periphery” — the rest of the body:

Insulin also plays a pivotal role in the control of appetite and feeding. In addition to its well-defined peripheral role in glucose clearance and utilization, insulin is involved in the afferent (and efferent) hypothalamic pathways governing energy intake, and in the limbic system’s control of pleasurable responses to food. Whereas insulin drives the accumulation of energy stores in liver, fat, and muscle, its role in the CNS tends to decrease energy intake. This is not a paradox, but rather an elegant instance of negative feedback. When energy stores abound, circulating insulin tends to be high; high CNS insulin tends to decrease feeding behaviors, thereby curtailing further accumulation of energy stores. Insulin’s central effects on energy intake are manifested in two complementary ways: first, insulin decreases the drive to eat; second, insulin decreases the pleasurable and motivating aspects of food.

This self-limiting regulatory action of insulin is also noted by Banks:

Insulin plays many roles within the CNS. Several laboratories have shown that some of the CNS effects of insulin are the opposite of those effects mediated through peripheral tissues. In particular, CNS insulin increases glucose and inhibits feeding, whereas serum insulin decreases glucose and increases feeding. Thus, to some extent, insulin acts as its own counterregulatory hormone, with CNS insulin producing features of insulin resistance.

Both insulin and leptin have an appetite suppressing effect when an elevated level of either one reaches the appetite center of the brain, specifically the satiety-inducing POMC/CART neurons within the arcuate nucleus (ARC) of the hypothalamus.  While similar in their appetite suppressing effect, insulin levels fluctuate in response to the ingestion of meals, especially carbohydrate-rich meals, whereas leptin levels generally reflects longer term changes in energy stores.   Most noteworthy for this discussion, however, these two hormones reflect the two different types of fat.  According to Woods et al:

Insulin is secreted in proportion to visceral fat, whereas leptin reflects total fat mass and especially subcutaneous fat. This is an important distinction with regard to the message conveyed to the brain, since visceral fat carries a greater risk factor for the metabolic complications associated with obesity than does subcutaneous fat. Elevated visceral fat carries an increased risk for insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and certain cancers. Hence, leptin and insulin each convey specific information to the brain regarding the distribution of fat, and the combination of the two additionally conveys information as to the total fat mass of the body.

Interestingly, Woods also reports the brains of females are more sensitive to leptin than insulin, whereas the reverse is true in males, and that estrogen mediates this difference.   According to  Cnop el at.women on average have three times as much leptin as men, even after controlling for comparable degrees of body mass and insulin resistance. Which explains why there are more male “apples” and more female “pears” — though of course both types of obesity are represented to varying degrees in both genders.

While the appetite regulating actions of insulin and leptin within the brain are well known, what is less well known is that these the two hormones also use “remote control” from within the brain to activate fat loss in the rest of the body.  According to Woods:

As previously mentioned, when leptin is administered into the brains of experimental animals, there is a selective reduction of body fat, with lean body mass being spared. Likewise, when insulin is administered into the brain, there is a reduction of the respiratory quotient, suggesting that the body is oxidizing relatively more fat. These observations suggest that one action of these adipose signals within the brain is to reduce body fat, and a corollary of this is that fat ingestion would be expected to be reduced as well. Consistent with this, we have observed that when insulin is administered into the third cerebral ventricle of rats, fat intake is selectively reduced. Hence, it is reasonable to hypothesize that leptin and insulin, acting in the brain, reduce body fat by increasing lipid mobilization and oxidation and simultaneously by reducing the consumption of dietary fat.

In short, if you want to control your appetite and burn fat faster,  you want leptin and insulin to get inside your brain!  The problem in obesity is that these hormones are not adequately reaching and communicating with the appetite center of the hypothalamus.

Putting up resistance.  So far, I’ve described how leptin and insulin work to homeostatically regulate appetite and body fat in normal individuals.  But this carefully balanced feedback system becomea derailed in obesity.  There are some interesting, but fortunately rare, genetic or disease conditions where the leptin or insulin sensitive receptors in the hypothalamus become defective and insensitive to leptin or insulin. In other words, the “off” switch for appetite stops working correctly.  Or where the leptin or insulin molecules themselves are mutated or damaged and are thus unable to turn off the appetite switch.  Animals or humans with these defects eat voraciously, insatiably and become extremely obese. These rare cases provided some of the initial evidence for the current understanding of how leptin and insulin regulate appetite and body weight.

But defective  hormones and receptors are rare and do not explain the vast majority of cases of obesity. The “normal” cause of obesity involves involves leptin resistance or hypothalamic insulin resistance, whereby there is plenty of leptin or insulin circulating in the bloodstream, and the appetite-suppressing POMC neurons are functional, but not all of the hormone is reaching the receptors in the hypothalamus. The messenger is yelling, but the ears hear the message faintly.  There is a barrier or impediment between messenger and receiver.   The result in each case is that appetite is not getting satisfied, so there is a drive to overeat.  And furthermore, as Woods notes, the “remote control” fat burning functions of the hypothalamus are also reduced.  As a result, with more eating and less fat mobilization and oxidation, you get fatter.

Now, let’s see in more detail what happens to the hypothalamus in each main type of obesity.

Subcutaneous (SC) obesity and the brain.  Leptin is produced in adipose tissue, but specifically in SC fat.  The more SC fat, the more elevated the leptin concentration in the blood.  Normally this would provide a negative feedback signal, inducing satiety in the hypothalamus and increasing the release of fatty acids from fat cells.  In SC obesity, however, only a low level of this leptin is reaching the hypothalamus, so appetite and eating are not inhibited.  But why does this happen?  What is the mechanism?

Some, like Lustig, see insulin resistance in the brain as a likely driver of leptin resistance:

Hyperinsulinemia itself may be a cause of leptin resistance. As described, insulin and leptin use many of the same neurons, the same second messengers, and the same distal efferents to effect induction of satiety….Although confirmation in animal studies is needed…CNS insulin resistance may be a proximate cause of leptin resistance, promoting continued weight gain.

However, it is not plausible to blame leptin resistance on insulin resistance, because many of the obese are insulin sensitive.  For example, Sumo wrestlers notably  can weigh 500 pounds or more,  but they are typically insulin sensitive, and have low cholesterol. According to an study by  Gerald Reaven of Stanford:

The ability of insulin to mediate glucose disposal varies more than six-fold in an apparently healthy population, and approximately one third of the most insulin-resistant of these individuals are at increased risk to develop cardiovascular disease. Differences in degree of adiposity account for approximately 25% of this variability, and another 25% varies as a function of level of physical fitness. The more overweight/obese the person, the more likely they are to be insulin-resistant and at increased risk of cardiovascular disease, but substantial numbers of overweight/obese individuals remain insulin-sensitive, and not all insulin-resistant persons are obese.

Recent evidence suggests that the crux of leptin resistance can be located at the door to the brain:  the blood-brain barrier (BBB).  The BBB is semipermeable along the arcuate nucleus.  This allows for controlled, selective transport of various nutrients and energy signals.  According to Banks,

The blood–brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation.

In a study on mice, Banks et al. showed  that triglycerides, but not free fatty acids, induce leptin resistance.  This same study showed that, that fasting for 16 hours reduced triglycerides and increased leptin transport, whereas fasting for 48 hours increased triglycerides and impaired leptin transport. This provides support for intermittent fasting as a strategy to reverse leptin resistance.  Elevated triglycerides also enhance the transport of ghrelin, the hormone responsible for initiating feeding at conditioned meal times, which explains why certain obese people get especially hungry around meal time.

Triglyceride levels tend to increase with your degree of adiposity.  But what causes them to rise in the first place?  The primary culprit seems to be fructose, which is converted to triglycerides if consumed in excess. Of course, fructose is part of sucrose and high fructose corn syrup, so any of these sugars in excess will elevate triglycerides, cause leptin resistance, and SC obesity.  Foods containing high concentrations of sugar include  sodas, candies, breakfast cereal, bread and other baked goods, but also sugary fruits like bananas, mangos and raisins. Michael Eades recognized the connection between triglycerides, the blood brain barrier and appetite in his 2007 blog post “Leptin, low-carb and hunger“. But I suspect that it is specifically the effect of fructose reduction — and not the generalized carbohydrate reduction postulated by Eades– that is the primary explanation for low carb diets work to reduce appetite so well for many people.

Diet, of course, is not the only factor affecting how the blood-brain barrier affect leptin resistance.  For example, Banks also notes that epinephrine enhances leptin transport across the BBB by a factor of 2-3 fold.  This explains why exercise and excitement can act to suppress appetite.

Intra-abdominal (IA) obesity and the brain.  Insulin is produced by the pancreas, when it circulates through most of the body outside the brain and spinal cord — what physiologists call the “periphery” — it’s main function is to regulate the availability and storage of glucose and fatty acids, thus preventing excessive glucose or fatty acid levels in the bloodstream.  When insulin receptors in liver, muscle, and other tissues become less responsive to insulin, the resulting insulin resistance results in hyperinsulinemia and its associated metabolic derangements such as Type 2 diabetes. There has been much investigation regarding what causes insulin resistance, the lead hypothesis being some sort of inflammation due to many suspects, including certain fats.

Unlike leptin, triglycerides do not impair insulin transport into the brain. According to a study by Urama and Banks,

[T]he triglyceride triolein significantly increased the brain uptake of insulin, an effect opposite to that on leptin transport, in starved obese mice….That is, leptin transport across the BBB increased with short-term fasting but decreased with starvation and with administration of triolein. In contrast, insulin transport is decreased by short-term fasting but increased by starvation and by triolein.


So what, if not triglycerides, leads to insulin resistance in the brain?

The answer appears to be: free fatty acids. Certain fatty acids – trans fats, certain long-chain saturated fatty acids, and omega-6 unsaturated fatty acids  — produce an inflammatory response in insulin receptors that blunts insulin sensitivity. By contrast, other fatty acids — principally omega-3 fatty acids (like flax or fish oil) and short or medium chain triglycerides (like coconut oil) — are actually anti-inflammatory).  Certain sugars like fructose also appear to be pro-inflammatory.  But what has not been recognized until recently is that these inflammatory processes occur not just in the liver and muscles, but also within the hypothalamus.

And in fact, inflammation of the hypothalamus may be where insulin resistance starts.

Posey et al found that mice fed a high fat diet, with equal calories to a low fat diet, gained 60% more adipose tissue than those on the low fat diet.  Other experiments by Kaivala et al. showed a high fat diet resulted in a 60% reduction in CNS insulin levels, inversely associated with changes in body weight. Thaler et al. , Schwartz et al and Benoit et al. showed that  one particular long chain saturated fatty acid — palmitic acid — causes inflammation and reduces insulin sensitivity in the hypothalamus, leading to overeating and obesity.  Arruda et al. found that intracerebroventricular  injection of an inflammatory cytokine (TNF-α) or stearic acid (another long chain saturated fatty acid) into lean rats induced insulin and leptin resistance in the hypothalamus and hyperinsulinemia and down regulated thermogenesis and oxygen utilization.  In TNF knockout rats (those missing the TNF receptor), the TNF-α did not produce any of these effects, and the rats were protected.  Furthermore, Araujo et al showed that co-administrering an anti-inflammatory drug (infliximab) restored normal oxygen consumption in the obese rats.  Similar results from other studies have been reviewed by Schwartz et al .

Interestingly, high levels of fructose can also cause inflammation and insulin resistance, leading to IA obesity.  If you are lean and healthy, fructose at reasonable levels is converted to glucose in the liver, and brief excess is then stored as glycogen in the liver and muscles.  But in vast excess, fructose is converted to fat of two types — triglycerides and one particular fatty acid.  Can you guess which fatty acid?  The answer is palmitic acid, the fatty acid associated with brain insulin resistance. The liver begins to accumulate the excess fat – a condition known as steatosis or fatty liver disease — which results in hepatic insulin resistance.   So while high fructose consumption causes elevated triglycerides, those triglycerides cause leptin resistance and are not a direct cause of insulin resistance. do not cause insulin resistance, only So it looks like fructose (and of course sucrose which is 50% fructose) is involved in the genesis of both SC obesity and IA obesity.  The fact  is just one manifestation of how easy it is to get confused about “the cause” of obesity.  Because there are two types of obesity with different but intertwined etiologies, the logic of obesity is not always so easy to sort out.  But the various diveres causal threads always come together in the arcuate nucleus of the hypothalamus

What is most illuminating, however, is research by Ono et al showing that hypothalamic insulin resistance precedes — and probably causes — insulin resistance in other organs and tissues.  Ono found that feeding rats a high fat diet induced insulin resistance in the hypothalamus after only one day, with no concurrent hepatic insulin resistance!  It took a full 3 days on this diet for insulin resistance to show up in the liver, and 7 days for the muscles and peripheral tissues to become insulin resistant.   The mechanism of inflammation was the activation of the mTOR/S6K pathway by exposure to fatty acids.  The S6K protein apparently inhibits insulin signaling in the arcuate nucleus of the hypothalamus, activating the orexigenic NPY/ArGP neurons and inhibiting the POMC neurons.  Similarly, Pagotta has marshalled other evidence suggesting that insulin resistance starts in the brain.  Of particular note is a study by Obici et al, in which central administration of insulin suppressed glucose production by the liver, and blocking insulin signaling in the brain impaired the ability of insulin to inhibit glucose production in the liver. Finally, an excellent post by Stephan Guyenet cites a similar study by Morton and Schwarz showing much the same thing.  As Guyenet notes,

Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin’s ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin’s ability to cause muscle to take up glucose is mediated by its effect on the brain.  

In regard to insulin signalling,  the brain seems to be in charge of the liver.  And this plays out in the genesis of insulin resistance.

This raises an interesting question:  why would insulin resistance start in the brain, rather than the liver or the muscles?  When you think about it for a few minutes, it actually makes sense.  The hypothalamus is the ultimate arbiter of whether or not the body has adequate energy intake. It does this by homeostatically regulating energy stores and energy balancing hormones. In the case of leptin resistance, as we’ve already seen, the brain acts to restore homeostasis signaling the peripheral metabolism to “grow” more subcutaneous fat (by increasing appetite and slowing fat oxidation).  If insulin signaling in the brain is blocked or impaired, homeostasis requires the initiation of compensatory processes that will bring more insulin into the brain.  But how to do that?  Insulin is not produced in the fat cells, so growing more fat won’t directly help.  To do this, the periphery must become somehow become hyperinsulinemic, in order to overcompensate so that enough insulin gets into the hypothalamus.  And the best mechanism for this is to induce whole body insulin resistance, primarily in the liver and muscles.

But how does the insulin resistant brain orchestrate insulin resistance in the periphery?  The answer, apparently, is to grow intra-abdominal fat. As Ljung notes, hypothalamic insulin resistance disrupts the hypothalamic-pituitary -adrenal axis (HPA), leading to increased secretion of ACTH and cortisol.  These hormones in turn stimulate the growth of intra-abdominal adipocytes.  The IA fat proliferates macrophages and releases pro-inflammatory  fatty acids and “adipokines” into the bloodstream. (See “Intra-Abodominal Adipose Tissue: The Culprit?“) The portal circulation carries these to the liver where they promote steatosis (fatty liver), insulin resistance, and local inflammation. The systemic circulation further carries these fatty acids and proinflammatory molecules to skeletal muscle where they promote lipid accumulation, insulin resistance, and local inflammation.  As Ross showed,  it is IA fat, not total fat or SC fat, that is associated with whole body insulin resistance.  Insulin resistance in the body causes the pancreas to go into overdrive to supply more insulin, resulting in hyperinsulimia. As basal insulin levels increase, the hypothalamus is now getting its fix of insulin, keeping hunger in check.  Of course, the level of IA obesity and hyperinsulimeia will only be what is required to handle the degree of inflammation experienced by the arcuate nucleus in the brain.  One this inflammation is reduced or removed, and the NPY/AgRP neurons become more sensitive to insulin, the requirement for elevated basal insulin should go down, and with it the need for intra-abodominal fat.


In slogan form, here is the Hypothalamic Hypothesis of Obesity:

If the hypothalamus is deficient in leptin, it directs the body to grow more subcutaneous fat.
If it is deficient in insulin, it directs the body to grow more intra-abdominal fat.


Now for some practical advice:   How can you use the Hypothalamic Hypothesis to lose unwanted fat or better control your weight?

1.  Start by assessing your degree and type of adiposity.  Do you have a waist-to-hip ratio greater than 0.8 (women) or 1.0 (men) and carry your extra weight a belly that sticks out in front? That’s IA fat and you are a probably an  “apple”. Or do you have a waist-to-hip ratio of less than 0.8 (for women) or 1.0 (for men) and carry most of your extra weight on your butt, your thighs, chest, and possibly also your arms and neck?  That’s SC fat and you are probably a “pear”.   Of course, you may be an “apple-pear” and carry extra fat in both locations, but it is good to know which type of fat is dominant.  If you want a much more precise assessment using specific measurements of body weight, height and other body dimensions, I recommend consulting “Assessing Your Risk”, Chapter 9 in Protein Power, by Eades and Eades.

2.  If you are primarily a “pear”, and particularly if you are significantly overweight, you are leptin-resistant.  Your primary focus should be on reducing triglycerides.  Largely, this means cutting back on carbohydrates with fructose or sucrose (which is a disaccharide of fructose attached to glucose) is readily converted to triglycerides by the liver.  And it is triglycerides that primarily induce leptin-resistant SC obesity.  So of course you want to cut out soft drinks, cookies, cakes, ice cream, candies, most fruits, and most breads (except those with no sugar, which are hard to find). But so long as you are reasonably insulin sensitive, you don’t have to cut out starches.  Potatoes and rice are probably fine if you are insulin-sensitive as long as you avoid any sugar in the same meal.  If you are an “apple-pear” and are resistant to both leptin and insulin, then you can still eat fructose-free starches like potatoes and starch, but you must not add any pro-inflammatory fats. The question of what constitutes a “pro-inflammatory fat” is a controversial one.  Some fats, such as trans fats and high levels of omega-6 fats are clearly pro-inflammatory, while omega-3 fats, mono-unsaturates like olive oil, and medium chain triglycerides like coconut oil are anti-inflammatory.  But for saturated fats, the picture is less clear and the studies are all over the place.  Probably some saturated fats are OK.  But some people have found that cutting back on cheese and nuts help them shed abdominal fat.  Milk and butter from grass fed cows may be preferable to that from grain fed cows.

What about alcohol?  Alcohol is frequently assumed to raise triglyceride levels, but observational studies show this may not necessarily not true.  Moderate alcohol may actually reduce triglyceride levels.

Finally, as the Banks’ fasting study suggests, intermittent fasting (16 hours, but not 48 hours) can reduce triglycerides and restore leptin sensitivity.

3.  If you are primarily an “apple”, pre diabetic, or trying to lose stubborn belly fat — the last 10-20 pounds,  your primary focus should be on eating a non-inflammatory diet.  For the most part, this means cutting back on certain fats — trans fats (anything “partially hydrogenated” on the nutrition label), vegetable fats high in omega-6 oils, and perhaps certain saturated fats like those in meat, milk, butter or cheese from grain-fed cows. As mentioned above, the question of which saturated fats are “pro-inflammatory” is controversial. The strongest evidence that connects saturated fatty acids to brain insulin resistance is for palmitic acid, but that does not mean all saturated fatty acids cause insulin resistance. In any case, don’t shun non-inflammatory fats like fish oil, olive oil, or coconut oil.  Adding these to your meals can help reverse IA obesity.  I’ve personally found coconut oil to be great for energy and weight loss.

Because consuming high levels of sugar in the diet (fructose, sucrose or syrups that contain them) causes output of pro-inflammatory palmitic acid,  foods containing sugar should be restricted.  If you are lean and have a have a healthy liver, I see nothing wrong with fructose in moderate quantitates.  The daily apple will not hurt you, but the excessive amounts of sugar in  sodas, pastries, ice cream, bread (which contains sugar)  sweet fruit — make you (or maintain you as)  both a  “pear” and an”apple”.

In addition to avoiding high levels of certain fatty acids and sugars, inflammation can also be reversed by a few additional steps:

Caveats. In making the above suggestions, I would like to make a disclaimer:  This post is primarily about a new paradigm of obesity, but I realize that people are looking for specific dietary recommendations.  The  above dietary advice is based upon my best attempt to interpret two general principles regarding the effects of triglycerides and inflammation on the appetite center of the hypothalamus.  In doing this, I am relying on a large body of empirical evidence that is sometimes ambiguous or contradictory — for example, regarding which saturated fats are pro-inflammatory, and which are protective.  And so I may be wrong about the hypothalamic effect of this or that specific food.  Despite this uncertainly, the HH provides a test for deciding whether a food or practice is obesogenic and leads to overeating: namely whether it raises triglycerides or inflames the hypothalamus.  And it is also apparent that these guidelines for foods to avoid cut across conventional macronutrient categories like “fat” and “carbohydrate”, since the hypothalamus does not sort things out that way.

OTHER THEORIES OF OBESITY.  I would like to close by contrasting the Hypothalamic Hypothesis with two other theories of obesity, showing how it better accounts for certain facts, and leads to perhaps some different recommendations for losing excess body fat.

The Carbohydrate / Insulin Hypothesis (CIH).  Most prominently advocated by Gary Taubes, CIH holds that dietary fat plays no role in obesity.  Rather, dietary carbohydrates, through their stimulation of insulin secretion, result in a greater degree of fat storage. Carbohydrates drive insulin drives net fat storage. Obesity is a disorder of excess fat accumulation, not overeating or inadequate energy expenditure.  In its favor, CIH can account for the close correlation between obesity and hyperinsulinemia, and the success of low carb dieting.  However, it manifestly does not explain why many obese people, like Sumo wrestlers, are insulin sensitive, with normal insulin levels and no indications of diabetes, cardiovascular disease, or other signs of Metabolic Syndrome.  It also does not account for why others, such as the Kitavans and Okinawans, can  eat a diet low in fat but high in certain starchy carbohydrates (polymers of glucose) like root vegetables or rice, and remain lean, with low basal insulin levels.  And it cannot explain why, despite sincere attempts, many people can lose only a certain amount of weight (probably subcutaneous fat) on low carb diets, but often stall and remain insulin resistant when continuing to eat a high fat / low carb diet.  The HH can explain all these facts by carefully distinguishing SC obesity from IA obesity, and by narrowing the cause of type of obesity to very specific types of carbohydrate (fructose and sucrose) and fat (long chain saturates, trans fats and omega-6 fats).  And, perhaps heretically, HH predicts that once you’ve maxed out the benefits of low carb, you can get rid of that paunch and insulin resistance by cutting back on fats– at least the pro-inflammatory fats.

The CIH also cannot explain certain anomalies such that described by Stephan Guyenet and Chris Masterjohn:  the LIRKO mouse which has severe hepatic insulin resistance and hyperinsulinemia — but remains leaner than its normal counterparts.  Guyenet and Masterjohn seem to conclude from this that insulin resistance cannot be a cause of obesity.  The mistake they make, I believe, is overlooking the possibility that only one type of insulin resistance — that of the hypothalamus — leads to obesity.  The LIRKO mouse they discuss had an insulin resistant liver, but apparently a well functioning hypothalamus.  It would have been interesting to feed it some pro-inflammatory fats to see what would happen.

One further aside about the CIH:  I must admit that I was previously persuaded by the orthodox version of CIH and it’s explanation about hunger–which I now suspect is incorrect.  I employed this theory elsewhere in this blog to explain the appetite-suppressing effect of low carb diets, intermittent fasting, and flavor control diets such as the Shangri-La Diet.  The explanation was based on what I thought was a very plausible theory I first encountered in Gary Taubes’ Good Calories, Bad Calories, Chapter 24,”Hunger and Satiety.” .  The insulin-lowering effect of low carb diets is supposed to counteract hunger from hypoglycemia by making glucose and free fatty acids more available.  And the appetite inducing effects of  appetitive flavors or aromas is explained by their action (probably via the vagus nerve, mediated by the brain’s  tractus solitarus) in eliciting a preprandial insulin response.  This preprandial insulin response supposedly causes a sudden drop in  blood glucose, inducing hunger.   I now believe this theory is wrong, or at least incomplete, for several reasons.  Primary among those reasons are my own experience with blood glucose self monitoring, where I noticed that my blood glucose would typically drop after, but not before I would get hungry.  Also, preprandial insulin responses are typically fairly small and unlikely to reduce blood sugar enough to induce hypoglycemic hunger. So the preprandial insulin response seems too little, too late.  It is more likely an effect, not a cause, of hunger.  I now suspect that a more likely explanation would be the direct action of the vagus nerve and tractus solitarus on the orexigenic or anorexigenic neurons in the ARC, or on the permeability of the blood brain barrier.  But that will be a topic for another post.

The Food Reward Hypothesis (FRH).  The most effective advocate for the FRH is Stephan Guyenet, of Whole Health Source.  Guyenet is the first to admit he is not the originator of this theory, which is common among obesity researchers and was prominently featured in David Kessler’s book, The End of Overeating. And Stephan also takes a modest stance in stipulating that he takes “food reward” to a be a major explanatory factor, but not the sole causal factor, for obesity. For example, he mentions exercise, leptin resistance, energy excess and, yes, even hypothalamic inflammation, as “other” contributory causes to obesity. So FRH is not supposed to be a monocausal theory of obesity. But modesty aside, Guyenet has put a stake in the ground and marshaled considerable argument and evidence in support of FRH.  Briefly, FRH holds that feeding people (or animals) foods have a high “reward” level results in overeating and obesity.  Here is how Guyenet defines “food reward”:

I use the term food reward to refer specifically to the motivational value of food, i.e. its ability to reinforce behavior.  For example, acquiring a taste that causes a person to seek out the food in question more often.  This is how some, but not all, researchers define the term.  Others use the term “food reward” to refer to both the motivational and the palatability value of food.  Palatability refers specifically to the enjoyment derived from a food, also called its hedonic value.  Palatability and reward typically travel together, but not always. (“The Case for Food Reward,” Oct, 1, 2011)

The theory is supported by experimental evidence, for example by the rapid weight gain seen with rats switched from ordinary chow to a  high fat, high sugar “cafeteria diet”, and further developed by referring to the effects of such diets on brain opioids, dopamine circuits and other neurochemistry. Guyenet goes on to propose a remedy for the abundance of super palatable food:  just say no.  By avoiding overly rewarding food, our brains can return to sane eating and obesity can be avoided or reversed.

I feel a certain affinity for the FRH theory because, like HH, it is a “brain-centric” theory of obesity.  Guyenet’s self-described field of research is “neurobiology of body fat regulation and obesity”, which I agree is the most promising way to study of obesity.  I’ve been excited to follow his cogent summaries of the most interesting research in this field. However, the FRH seems to have incorrectly formulated the connection between the brain and obesity.  In fact, I’ve already discussed the FRH theory in another post, “Does tasty food make us fat?.   Here is what I wrote there:

But I think the theory is wrong, for the simple reason that it too blindly takes correlation for causation. And in doing so, it gets the causal direction mostly wrong. We don’t get fat because food has become too tasty. Rather, to a large extent, it is the metabolism and dietary habits of the obese that make food taste too good to resist, leading to insatiable appetites. And the good news is that we are not consigned to blandness.  If we eat and exercise sensibly, we can eat flavorful, delicious foods and enjoy life, without packing on the pounds.

I had not formulated the HH theory when I wrote that post, but it fits the bill of what I said there: it is the metabolic effects of the pertinent foods in “cafeteria” diets that make them “rewarding” and engender the secondary effects on pleasure-related neurotransmitters like beta endorphin, dopamine or serotonin.  What HH does is to more specifically locate the primary metabolic effects within the arcuate nucleus of the hypothalamus, rather than elsewhere in the body.

I think that HH can explain a number of things that FRH cannot.  FRH is a somewhat vague in that it does not go very far to identify what specific attributes of food make them rewarding and what specific mechanism are involved.  Somehow, sugar, fat and salt are involved. It is more like a schema than a full theory, which makes it hard to test or criticize. By contrast, HH is very specific about the mechanisms by which specific food chemistries interact with specific parts of the brain.  HH,  unlike FRH, provides an explanation for why certain “rewarding” foods will eventually lead to  either subcutaneous obesity or rather intra-abdominal obesity.   HH holds that if you are neither leptin resistant or insulin resistant, then no foods will be inherently hyper-rewarding, at least initially.  Foods only become hyper-rewarding once insulin or leptin resistance begins to manifest itself.   HH makes the further prediction that very tasty, palatable foods that contain no fructose or sucrose (or other agents that elevate triglycerides) or pro-inflammatory fats, will not lead to obesity, no matter how good they taste.

A wider perspective: The homeostatic pleasure principle.  Finally, I think that the Hypothalamic Hypothesis provides a way to connect the hormonal regulation of obesity to something overlooked by both CIH and FRH:  the role of emotion and cognition in obesity, and the relation of obesity to our wider sense of well being.  Obesity is often a response to emotional factors like stress and depression, and conversely might be reversed by cognitive techniques such as cognitive reframing and meditation.  By locating the original of obesity within the hypothalamus, it becomes plausible to understand how stress hormones like cortisol and or calming neurotransmitters like serotonin can have a powerful and direct effect on the behavior of hypothalamic neurons and their sensitivity to leptin and insulin, since these neurochemicals are lurking nearby within the “neighborhood” of the brain.  Looked at more broadly, the hypothalamus can be thought of as a homeostatic regulation system that attempts to maintain an internal subjective sense of well-being or pleasure with respect to a broad range of drives, including not just eating, but sleep, sex, aggression, fear and other emotions.   This  homeostatic “pleasure principle” is fundamental — its provides a way to translate objective needs of the organism into conscious desires and emotions.  This fits into a related line of thinking about brain receptor sensitivity that I wrote about in my post “Change your receptors, change your set point“.  Whenever there is a dysregulation of the pleasure principle, such as occurs in the appetite drive of obesity, but also in conditions such as depression or addiction, we should look within the control system itself to find out what is going wrong. And that is what the HH does, by looking for specific brain mechanisms that explain not only our subjective experience, but the way the rest of the body responds objectively in homeostatic response to physiological disturbances.

Like this article or disagree with it?  Add you comments below, or join the more extended discussion in the Discussion Forum.


  1. I am thrilled that you’ve added this to the discussion! Between your hypothesis and J. Stanton’s work on hunger, I think we’re going to be able to get to a better place than we would just debating CIH vs FRH ad nauseum (I can’t wait to hear Paul Jaminet’s take on this too … I know he’s got something planned soon).

    As an aside, one thing I especially like is how your theory maps with the often-prescribed advice to avoid fruit and dairy while in weight-loss mode. A bit of an ‘a ha’ moment for me!

    One question. Given that visceral fat is really the more harmful of the two types of adipose tissue and that your garden variety heavy pears likely have both, wouldn’t it make sense to address both types at the same time? Seems easy enough to do.

    • Todd

      Thanks, Beth. I agree that pursuing the combined set of weight loss recommendations makes sense for those who struggle with both subcutaneous and abdominal obesity. But since many people have one dominant type and may not want to be more restrictive than necessary, I wanted to suggest where to start based upon what the theory and research says.

      As a caveat, I do also want to say that I have more confidence in the general theory (reducing blood triglycerides and pro-inflammatory foods) than the specifics regarding which particular foods to restrict or emphasize. For those recommendations, I am to a large extent drawing on the work of others regarding which foods give rise to those consequences. There may be legitimate debate, for example, regarding which fats cause inflammation, or whether alcohol raises triglycerides. I think it is more important to understand the general principles here and combine these with general dietary knowledge to arrive at a plan for yourself.

  2. majkinetor

    Good article, but any theory of obesity that doesn’t include endo/exo cannabinoid system is not complete. No amount of leptin/insulin sensitivity will protect you from munches.

    So, HH hypothesis is partial explanation at best.

    • Todd

      @ Majkinetor

      Thanks for bringing this up. It is important to distinguish short term vs. long term appetite signals. In addition to your example of cannabinoids, hormones like ghrelin or cholecystokin signal meal initiation or stomach fullness. But unless these short term signals are somehow continuously sustained, I don’t see how they could override the leptin and insulin signaling which reflect long term energy status. Cannabinoids might explain a temporary increase in appetite, but if the insulin and leptin signaling are working, any weight gained this way would eventually come back off once the fat tissues get their sustained message through to mission control in the hypothalamus.

      • majkinetor

        To be precise, Anandamide works in hypothalamus too but CB1 receptors are more frequent in other parts of the brain and there are lots of them peripherally.

        Anandamide modulates effects of both ghrelin and leptin and it looks like it mediates other related things, like reproduction, adipocite proliferation and inflammation etc…

        It also looks like w-6 promotes it synthesis.



        • I too am intrigued by endocannabinoids and appetite (http://weightmaven.org/2011/04/21/our-western-diet-prescription-for-disaster/).

          As far being continuously sustained, if the problem is linoleic acid consumption (via Western diet) in the presence of met syn/high fasting insulin, then it could certainly be a contributor. And in “Endocannabinoids and energy metabolism”* the authors noted that compared “to the degree of overeating induced by THC, AEA [anandamide] displayed a reduced potency, but its effect was longer lasting.”

          Stephan has briefly touched on this in the past but is not as intrigued as I; I suppose that says something ;). But I remain curious about it.

          * http://diabesity.eu/documents/FinalJEIIssue.pdf

        • majkinetor

          Beth, the problem with it is that CB1 is discovered in 90es and so the science is still young. Its also very hard to measure since it looks like it is manufactured on demand. There are tones of anecdotal data given that there are number of countries that have liberal marijuana usage (including pregnancy).

          Everybody overeats on marijuana, particularly carbs. There seem to be 2 phases – acute phase which lasts for few hours and longer lasting phase that starts after first one and lasts for 1 or 2 days (increased appetite, carbs mainly). For that very reason its used in cancer and AIDS. CB1 antagonists may reduce eating so much that lil rats refuse to suck milk and die.

          I checked the story on the link you posted as soon as it was published – I wanted to see if dietary PUFA means higher levels of endocanabionids, and indeed, there is evidence that it is so.

  3. Hi Todd,

    You said:

    “Finally, as the Banks’ fasting study suggests, intermittent fasting (16 hours, but not 48 hours) can reduce triglycerides and restore leptin sensitivity.”

    Your recommendation of fasting for SC obesity in fact does not aknowledges the fact that there is evidence that short term fasting changes the distribution of fat, ie. from visceral towards SC:

    “After 4 weeks of diet, the proportion of visceral fat decreased (P<.001) and the proportion of subcutaneous fat increased (P<.001) similarly in ADF [alternate day fasting] and CR [calorie restriction] animals. Adiponectin increased (P<.05) by 62-86% in the ADF groups and by 69% in the CR group. Triglyceride (TG) synthesis and de novo lipogenesis were augmented (P<.05) in the subcutaneous fat pad of ADF and CR animals, relative to control. No differences in net lipolysis were observed, resulting in greater TG accumulation in the subcutaneous fat pad, with a shift in the ratio of TG between depots. (http://www.ncbi.nlm.nih.gov/pubmed/19195863)"

    Also, as I understand, you recommend "apple" persons to avoid some fats but not carbohydrates directly, which conflicts with some evidence on the differential response of SC and IA adiposity to glucose:

    "Glucose uptake was associated with increased expression of FDPs [fat-derived peptides], including resistin ( approximately 5-fold), adiponectin ( approximately 2-fold), leptin ( approximately 15-fold), plasminogen activating inhibitor-1 ( approximately 10-fold), and angiotensinogen ( approximately 4-fold) in visceral fat, but markedly less in subcutaneous fat. "(http://www.ncbi.nlm.nih.gov/pubmed/15734842)

    So while you may be technically accurate, the practical implications may be useless as both types of obesity respond favorably to carbohydrate restriction.

    • Todd

      @ Lucas,

      Thanks for challenging me on these points – helps me stay sharp.

      Intermittent fasting (not eating for 12-20 hours a day) is something I recommended in my post for BOTH apples and pears. The Banks study showed fasting to be effective in reducing TGs (hence SC fat) after 16 hours fasting, but it increases TGs after 48 hours fasting. Your Varady paper studied alternate day fasting (ADF), which is 24 hours, so that is somewhere in between the 16 and 48 hours. So we don’t know, based upon Banks, what is happening to triglycerides at that point. Furthermore, the Varady study claims only that “After 4 weeks of diet, the proportion of visceral fat decreased (P<.001) and the proportion of subcutaneous fat increased (P<.001) similarly in ADF and CR animals." That doesn't mean that the absolute amount SC fat did not decrease, only that its relative percentage of total fat increased. So if a mouse started with 10 grams of IA fat and 10 grams of SC fat, but after fasting ended up with 9 grams of SC fat and 6 grams of IA fat, then it would have lost 2 gram of SC fat but increased its SC fat percentage from 50% to 60%. The fact that IF may work differentially better to reduce IA fat than SC fat does not mean it isn’t nevertheless effective in reducing SC fat.

      LIkewise, I don’t think the Einstein paper contradicts the HH theory. The Einstein et al. study was carried out under conditions of forced feeding of glucose to intentionally induce hyperinsulinemia and insulin resistance. So I’m not sure how relevant that is to a normal situation of moderate glucose consumption consistent with insulin sensitivity. More importantly, the ABSOLUTE baseline level of leptin in the visceral adipocytes was far lower than that of the SC adipocytes, so the fact that, upon glucose feeding, the percent increase of leptin expression was higher in the SC vs. the IA adipocytes means very little. At the end of the day, the SC fat cells as a total fat depot still produced a higher absolute level of leptin than the visceral depot. And that is consistent with dozens of other studies showing that leptin is mostly produced in subcutaneous fat.

  4. Melinda

    Wow Todd,
    This is a great post. Much food for thought. Helps explain experiences I’ve had with weight gain/loss. I was an apple and eventually a pear as well. I started VLC when I read GC,BC and lost >50# but 3 years later I developed thyroid problems and tried adding “safe” carbs back in ala PHD, helped. Now I’ve been trying the Leptin Reset and it has helped me lose most of last winter’s weight gain but I’m still not back down to my lowest post GC,BC weight loss. Your ideas will give me a road map forward to self test. Thank you very much.

  5. Very good article, but the theory about leptin being a master hormone, and its effect on obesity, was first promoted publicly by neurosurgeon & Paleo dieter Dr Jack Kruse during the last 1-2 years. Some don’t believe him, others do. I’m one of these who do believe in his and your hypothesis.

    • Todd

      @ Eugenia

      You are correct that the leptin theory is an old one. In fact, it goes back much further than Jack Kruse. In 1995, Jeffrey Friedman discovered and publicized the role of leptin in fat regulation. And in 2002, Byron Richards came out his popular book, Mastering Leptin.

  6. Can you do a followup post with a list of “good” and “bad” foods for Apples?

  7. Hi Todd. I appreciate the way you try to stay open and account for all the phenomena, adjusting your understanding as you need to when new information comes along.

    Hey, I’m a bit confused by your theory, though. Fructose seems to be a problem.

    My understanding is that Fructose is one of the easiest ways to raise trigs, which on the HH would lead you to expect it to lead to SC fat accumulation. However, this study seems very clearly to indicate that fructose leads much more to visceral fat accumulation:


    • Todd


      Thanks for sharing the paper. Fructose has a dual role that perhaps I should have highlighted in my original post. In dietary excess, fructose gets converted bv the liver not only to triglycerides, but also to palmitic acid, causing systemic inflammation. I believe it was this additional inflammatory effect — not the coincident elevation in triglycerides — that caused the subjects in the Stanhope study to gain IA fat.

      The paper by Stanhope et al had two interesting features: it was conducted in obese/overweight humans and it studied fructose vs. glucose at extreme levels – 25% of caloric intake! Stanhope showed that high fructose consumption significantly increased triglycerides and IA fat, but only modestly increased SC fat, whereas high glucose consumption had only a minor effect on either. The effect of the fructose on triglycerides is just what the HH theory (and many studies) predict. But from the paper I cited by Urama and Banks, we know that triglycerides don’t impair brain insulin sensitivity; if anything they improve it. So most likely it was elevated palmitic acid or other inflammatory effect of fructose that caused the IA fat to increase so dramatically. And studies by Cnop, Reaven and others establish there are many obese insulin sensitive people with high triglycerides who have little IA fat and are not insulin resistant. It would have been interesting to administer an anti-inflammatory drug to the subjects in this study. The study I cited by Araujo et al suggests that would have blunted the gain of IA fat.

      While IA and SC obesity have separate pathologies, they often co-exist in the same individual and can arise from a common causal agent like fructose, but for different reasons.

      Your question was an excellent one. It impelled me to go back and modify my post to point out this dual role of fructose in both branches of the obesity problem.

      • majkinetor

        You can’t compare animal and human studies when fructose is in question. Fructose stops vitamin C synthesis in animals and will, because of that, lead to inflammatory conditions.

        Furthermore, if there is a defect in beta oxidation pathway it will induce fatty liver disease which will further promote inflammation.

      • Nice article Todd!

        I had the same question about fructose and body fat distribution. I guess I’m not sure what you’re getting at with the difference between the fatty acids made by DNL from fructose vs. triglycerides, because the FA’s made by DNL in the liver are packaged up into the VLDL put out by the liver. This seems to favor visceral fat deposition.

        Lots of food for thought in this post! KUTGW 🙂

        • Todd


          Thanks for your good comment. As you can probably tell, my thinking on these issues around obesity has evolved and has benefited from my earlier interchanges with you, as well as what I’ve learned from your blog and others such as Whole Health Source, HyperLipid etc. In my article above, my confidence is probably stronger regarding the general thesis than it is for some of the specific details. What I mean by that is that there is an abundance of evidence that the hypothalamus is the “integrator” of information from peripheral signals, including nutrients, hormones and various neuropeptide signals (including probably conditioned responses to “reward” cues like flavor), and that hypothalamic neuron activity modulates not only subjective appetite, but also — most interestingly and surprising to me — the hypothalamus in turn modulates peripheral activity in the adrenals and digestive system — hence the so-called HPA (hypothalamic-pituitary-adrenal) axis. Certainly it is a complex regulatory network, but I think the evidence is that the hypothalamus is in charge of the show.

          At a somewhat more specific level, it appears that leptin and insulin play a very strong role in this hypothalamic regulation in this sense: in normal weight people, variations in glucose, fatty acids, ghrelin, CKK, etc., reflect transient changes by the hour, whereas leptin and (basal) insulin reflect a longer term, more stable assessement of body energy stores in adipose tissue. So leptin and insulin are the two regulatory signals to pay attention to if you want to understand brain-driven obesity. And the evidence suggests that obesity occurs when leptin or insulin signalling become impaired. That can happen for a number of reasons, including defective leptin molecules, inflamed receptors, receptor inhibition or downregulation, or diffusional barriers, e.g. in the blood-brain barrier. Adding to this, the type of obesity (SC vs. IA fat) seems to be determined by whether it is primarily leptin resistance or hypothalamic insulin resistance (as opposed to other types of IR) that is involved.

          I’m fairly confident in the foregoing “general” story, based upon the studies I’ve reviewed. Where I’m less certain is in the specific details of which food molecules cause hypothalamic inflammation or downregulation, and which ones lead to brain leptin or insulin resistance by diffusional barriers at, e.g. the BBB. The research by Banks connecting triglyceride effects on the BBB with leptin resistance seems right to me, although Stephan expressed some doubts about it in his earlier comment. And there is a fair bit of support for certain isolated molecules like palmitic acid resulting in inflammatory IR in the hypothalamus, But it is fair to challenge the relevance of those studies for reasons such as the one you raise about the “packaging” of FAs in VLDL. Does palmitate-rich VLDL in the blood release any free palmitate at the BBB that can enter the hypothalamus? I assume that in the blood there are always free fatty acids in equilbrium with triglycerides or VLDL forms, but I’d love to have someone inform me about this. And is fructose more of an actor in producing triglycerides that impair leptin transit through the BBB, or does it have a greater “inflammatory” effect via free palmitate? And does that depend on genetics, degree of being fed vs. fasted, etc.? These are all questions worth answering.

          To sum up, what I’ve offered here is admittedly more of a framework than a complete story. For that reason, I’m quite interested to hear objections or alternative scenarios regarding the details. I could have spent another month studying this to get it right, but I figured that this is why we have the Internet and blogs — as long as we have folks willing to learn, challenge and contribute to the evolving story.



        • Thanks for the explanation Todd. Personally I’m not after one unifying hypothesis for all of this, though I find the idea intriguing. It’s more does the evidence/data fit the hypothesis. Banks’ work seems convincing but then I wonder how do 24 hour profiles fit in here. I just came across a study that indicated acute insulin suppresses VLDL generation by the liver.

          I definitely have to spend more time re-reading this and the references. I’m especially interested in the pear v. apple thing. I always gained as a pear until I tried LC my first time in my early 30’s. Even when losing weight there was a noticeable difference — weight stayed around my midsection where that is where I used to lose first. Few more cycles later, and I’m much more apple after LC’ing. Was I LR now IR? Pass the fruit cup 😉

        • DancinPete

          What do you think about this blood flux theory of abdominal fat accumulation? Basically he’s suggesting that as the liver is used to remove toxins out of the blood (fructose, alcohol, caffeine etc.) more blood is flowing through the abdominal area, which exposes the organs to a higher amount of TGs than the periperal areas.


  8. Luke


    Have you read the article on The Gladiator Diet that appeared in Archaeology? Appears the gladiators needed plenty of subcutaneous fat to protect them from cut wounds and to protect their nerves and blood vessels. It’s an interesting read and can be found at: http://www.archaeology.org/0811/abstracts/gladiator.html

  9. Todd:

    This is an intriguing article: I like the “leptin resistant obesity vs. insulin resistant obesity” distinction, with leptin resistance being more triglyceride-driven and insulin resistance being more inflammation-driven.

    The tricky part of all this, of course, is figuring out which factors are driving a homeostasis and which factors are compensating. I don’t think I’m as convinced as you are that the brain (or, in this case, the hypothalamus) is first cause — but I appreciate your work. You’ve drawn a useful set of connections, and I thank you for bringing them to our attention.


    • Todd

      Thanks for weighing in here, J. I admire your blog at gnolls.org and your efforts to understand “likes”, “wants” and the other details of appetite. You are certainly right that brain and endocrine circuits are complex, so it’s hard to find the control point. Despite the apparently complexity, most complex adaptive systems (like mammals) do have a main control point. I think that in the case of drives like appetite, sleep, and sex — as well as functions like body temperature — we all have a central “thermostat”, and it is the hypothalamus. At this point it is still a hypothesis, of course, but it is one that I think is plausible enough to be worth checking out.

  10. Hi Todd,

    Excellent article. One question: You mention that Palmitic acid causes inflammation, but also that Coconut oil is anti-inflammitory. According to wikipedia, “As its name indicates, it is a major component of the oil from palm trees (palm oil, palm kernel oil, and coconut oil).”

    Am I missing something here? or is the anti-inflammitory effect of CO overwhelming the inflammitory effect of the palmitic acid it contains? If so, would we be able to separate the palmitic acid out of the coconut oil and just get the anti-inflammitory component?


    • Todd


      Actually, coconut oil is harvested from the coconut palm, which is not the same tree as a “palm tree”. About 85% of coconut oil is mostly “medium chain” triglycerides with less than 16 carbons. The dominant fatty acid–about 50%– in coconut oil is lauric acid (about 50% of the total). Less than 10% of coconut oil is palmitic acid. (Keep in mind that in the case of fatty acids, it is the overall balance of the blend that matters, so the presence of a small amount of palmitic is not a problem). The medium chain triglycerides in coconut oil bypass normal intestinal digestion and pass directly to the liver, where they are converted to energy.

      Coconut oil has a wide variety of health benefits. For some great research and practical advice on the use of coconut oil, I’d recommend Sally Fallon’s book:

      • Stipetic

        Concerning the inflammatory properties of palmitic acid, I find it intriguing that nature chose to package it with oleic acid, while endogenous production does not (I believe Peter at Hyperlipid has addressed this in the past). When packaged with its buddy, palmitic acid doesn’t appear to be inflammatory. When studied/produced in isolation: pro-inflammatory. Maybe this is another great example of the body’s highly intricate communication system where the nature-packaged goods signal health, while endogenous production of solitary palmitic acid sends the opposite signal.

        I’m curious, are you aware if the pre-prandial insulin spikes (glucose dips) of the obese are more sensitive than yours/non-obese?

        Enjoyed reading this post greatly.

        • Todd


          You are quite right that studies of the metabolic effects of single fatty acids in isolation are not representative of the effects that naturally-occuring heterogenous mixture of fatty acids. Saturated fatty acids pack differently in membranes when mixed with more fluid “curve” mono- and poly- unsaturates and shorter chain saturates.

          Given the data on pure palmitic acid, I would be most concerned with (a) very high fructose consumption — since palmitic is the only fatty acid produced from fructose by the liver; and (b) fats that are “unnaturally” high in palmitic acid.

          Studies of grain fed vs. grass fed (or grass finished) beef show a marginally lower palmitic acid percentage in grass fed beef, but much lower absolute palmitate content, since the beef is leaner. Of possibly greater important, the grass based diet results in dramatically lower n-6/n-3 ratio, meaning less inflammation.

          Presumably, the improved fatty acid profiles of grass fed cattle should extend to dairy products like milk and butter.

          Regarding the exaggerated preprandial insulin spikes of the obese, I wrote about this in my Diet post and illustrated it with a figure I borrowed from Bert Herring’s Fast-5 Diet book.


  11. Todd, again, thank you for presenting this synthesis.

    I have some further questions.

    In his latest article (the reply to Taubes’s series) Stephan linked to a bunch of studies that suggest flavor is a major reward factor and leads to fat accumulation in clinical trials (some animal, some human).

    Here is a link to the first (I’ve only read the abstract, but I find it very suggestive).


    The key there is that the macro content of the treatment diets were identical, and only flavor varied.

    I think it would be well worth your time to take a careful look at all 6-7 articles Stephan links to (in the first set of references in his reply to Taubes). You may have already. I don’t mean to suggest you haven’t. But IF you haven’t, then you should 🙂

    I’m coming to the conclusion that obesity is a function of both reward and metabolic effects.

    As for the metabolic effects, as you say, the hypothalamus, and the amount of leptin and insulin signal that gets through appears to be key. And the key culprits, as you also say, are probably high trigs and inflammation caused by things like fructose and linoleic acid (and maybe gluten and other things that Kurt Harris refers to as “Neolithic Agents of Disease”.).

    But I think Stephan has made a wonderful case that food reward is part of the story as well. (as do Kessler, and Schwartz, and others)

    One question I have is whether the dopamine/addiction behaviors operate in parallel competition with the normal hypothalamic determinants of body fat levels, or if they actually affect the hypothalamus, ARC, POMC, NPY system through the nerve connections that run between these areas and the reward centers.

    Either way, I’m leaning toward both being big factors (personal experimentation supports this as well). I think Stephan actually leans that way as well. Although I won’t presume to speak for him, I think I’ve seen enough on his blog to make an educated guess that he’s open to some metabolic factors being partial causes of obesity. He definitely sees leptin and it’s effect on the hypothalamus as being a key to normal body fat regulation. And he points out how many of the genetic anomalies associated with obesity involve leptin signaling. I don’t ever see him ruling out metabolic factors in principle affecting leptin signaling as being part of the problem. (Though he does rule out one metabolic theory in particular, as we’re all well aware of now 🙂

    So, I’m not sure how much your HH differs from his FRH, unless you’re prepared to deny that food reward is much of a factor at all. Though, I do have to say (in favor of your claim to originality) that this is the first I’ve seen the association between visceral fat and hypothalamic insulin resistance and SC fat and hypothalamic leptin resistance. That’s very interesting stuff there, and will rattle around in my head as I continue to consume information on this topic.

    • Todd


      Yes I have read Guyenet’s very interesting “rebuttal” to Taubes, and I have read some of the same references you mention. I certainly do acknowledge a strong connection between flavor and appetite, as you will see from my posts on Flavor control diets and my Deconditioning Diet. Much of my interest in the science of appetite and obesity started after reading Seth Roberts book on the Shangri La Diet, which is all about appetite suppression. My emerging view is that the perception of flavor, particularly reinforced flavor, comes into the hypothalamus directly via the tractus soliltarus and the vagus nerve by means of a number of different neuropeptides. To answer your question, I believe this signals directly modulate the action of the NPY/AgRP and POMC/CART neurons on appetite and peripheral metabolism. In addition, other signals from the gut, such as CCK are integrated within the hypothalamus to modulate appetite. So the hypothalamus is “Grand Central Station” for integration of signals that include nutrients (glucose and fatty acids), energy hormones (insulin and leptin) and other sensory signals for fullness, etc. I’m putting all of this together in an upcoming post. I still see leptin and insulin as the “trump cards” in this integration for a few reasons. First, they are persistent signals (so long as they are not blocked) that reflect the relatively stable energy status of the organism. Second, because the evidence is that if your leptin and insulin levels are high (and get through to the hypothalamus), this overrides other appetitive cues such as food aromas that would normally stimulate appetite.

      In some ways you could argue that the HH theory is a specific version of the FRH theory. Perhaps so, but it seems to me a much more specific and testable theory that actually locates the center of action and the mechanisms involved. And it doesn’t say anything about the two types of obesity or the role of specific hormones. This may be where Stephan Guyenet is going or what he has in mind. Certainly he has written about this and is an expert in the field of neurobiology. But I haven’t seen it pulled together in a unified model yet, so that is why I have put the Hypothalamic Hypothesis out there.


      • I’m sorry J. Stanton took his hiatus when he did, as I think the role flavor plays in appetite is most related to the “learning” part of his “liking, wanting, learning” trilogy … and I thought he planned to talk more about that.

        Clearly we have taste buds for a reason, even if they are relatively limited (most flavor is signaled thru smell). Flavorful things likely trigger some evolutionary “eat more” signals. And while I’m not sure about the chugging of sugar water or flavorless oil, I think Seth Roberts makes a good point about the success that industrial food producers have in providing these hyperpalatable substances that taste exactly the same (e.g., a Big Mac that tastes the same everywhere reinforces the learning aspect of the reward).

        • Todd


          I certainly agree with you that flavor is central to appetite. One of the simplest ways to prove that, as Seth Roberts and others on his website discovered, is to clip or pinch your nose while eating. This dramatically suppresses appetite and is a powerful–if perhaps inconvenient–way to lose weight. This is also the basis for Roberts’ own theory of flavor-calorie association, in which classical (Pavlovian) conditioning drives a learning process that, according to Roberts, controls “set point”. My own view is that Roberts is qualitatively correct in his observations, but that the theory needs to have an underpinning in terms of real, physiological and neurobiological mechanisms. What I’m attempting to do with the Hypothalamic Hypothesis is fill in the mechanistic details. Without this level of detail, I’m afraid that the Food Reward Hypothesis is too schematic and difficult to validate empirically, bordering on being circular (i.e. we eat too much when we eat rewarding food, and rewarding food is that which we are inclined to eat too much of). The interesting question is: what specifically is it in the food and in the brain that makes the food rewarding to the brain? And does it start out that way with food being inherently rewarding from the start, or does the brain change after consuming the food for a while to make the food become rewarding. That’s what we need to know. We already know we eat too much rewarding food!

      • Thanks for replying again Todd.

        I have been aware of the theorizing you’ve done in response to Seth Robert’s stuff. I was right in there with you trying to push a pre-prandial insulin explanation of Seth’s observations, back when I, too, was under the influence of Mr. Taubes.

        I read your flavor-diet review, too, and found it quite interesting. I think Seth, you, and David Kessler might have played a role in making me especially receptive to Stephan’s food reward ideas when he started presenting them (though it was also largely due to the excellent job he did in making his own case as well).

        I have so far found your attempts to integrate different observations and hypotheses to be quite interesting. I recognize my own thinking processes in the stuff you write. Whether your attempts to synthesize turn out in the end to be correct or not doesn’t matter much to me, because I’ve observed that you’re the kind of guy who can change your mind if the weight of evidence starts to take you in a different direction.

        As for the topic I started with, . . . I see that Dr. G has weighed in below, so I’ll not push this particular line any further 🙂

        • Todd

          Thanks, Jim. While I do make an effort to develop a consistent framework, especially at the most general level, I’m ultimately persuaded by empirical data. I also like to read those who offer a contrary view for the same reason I like physical hormesis — because challenge and adaptation to reality can only strengthen you. So yes, I will change when the evidence calls for it, particularly if it involves mere details. Although sometimes I’m a bit stubborn and need to double check the evidence and take a while to think about all the ramifications of changing direction. Sounds like this describes you too!

        • Yes sir! Keep up the good work.

  12. Kindke

    Nice post, great to see others paying attention to the POMC/AgRP neuron part of obesity. Im almost certain that obesity starts in the brain, when you look at MC4R mutation people, how obese they are, and consider that AgRP blocks the MC4R receptor, things should be obvious how important the brain is in obesity.

    There is a strong relation with GLP-1 here too, fats consumed alone produce GLP-1, but fats consumed with carbs dont produce any GLP-1.

    Blocking the GLP-1 receptor makes you obese meanwhile administering GLP-1 agonists reverses obesity independent of calorie intake.

    The link is that the POMC neurons sport GLP-1 receptors.

    As a further interesting tid-bit, the people who suffer from MC4R mutations seem to benefit from Roux-en-Y surgery which is notorious for causing hypersecretion of GLP-1.

  13. Hi Todd,

    Nice post. Here are my comments, as per our e-mail exchange.

    Body fat homeostasis is regulated by a distributed network of brain areas in the hypothalamus that includes the arcuate, but also several other regions (particularly the ventromedial hypothalamus, lateral hypothalamus, paraventricular nucleus). These are interconnected with other brain areas that process satiety/satiation, reward/hedonic drives and a variety of other things.

    The leptin resistance that is observed in diet-induced obesity is thought to come from at least two sources: lowered blood-brain barrier permeability to leptin/insulin, and an intrinsic resistance of hypothalamic neurons to these hormones (NPY and POMC neurons, among others). The former appears to occur early, and the latter soon joins it.

    The BBB permeability hypothesis is interesting, but it isn’t nearly as well developed as the hypothesis that leptin resistance intrinsic to hypothalamic neurons contributes to obesity. I have read Bill Bank’s papers, attended lectures by him and discussed it with him in person, and he seems like a solid scientist to me. However, there are certain aspects of the hypothesis that remain unanswered. Triglycerides don’t just float around in the circulation, they are contained in lipoproteins, and it has never been shown that triglyceride-rich lipoproteins (VLDL and chylos) can decrease BBB permeability. Banks has some evidence to suggest that increased trigs in vivo correlates with lower BBB permeability in certain cases such as lipopolysaccharide exposure, which adds to the case, but these are correlative studies.

    It has never been shown that if you block the decrease in BBB permeability you can attenuate leptin resistance and obesity, but it has been shown many times that if you interfere with the mechanisms of leptin resistance that are intrinsic to hypothalamic neurons (e.g., PTP1B, SOCS3, MyD88, IKKbeta), you can attenuate the development of obesity in rodents. I think Banks’s idea is interesting and it may well be true, but it’s going to require some more work to solidify it in my opinion.

    Regarding food reward, the reason I like it so much is it complements the shortcomings of a solely hypothalamus-based model. For example, it is difficult to explain why Americans eat ~400 more calories than they did 40 years ago using only a hypothalamic model. We eat more sugar and refined carb (junk food) than we did back then, but why? What caused us to eat more of these foods to begin with? There were no major changes in the composition of the US diet during the 80s that could account for direct effects on the hypothalamus, but what changed radically is the way our food was presented. The hypothalamic model, although undoubtedly correct, is incomplete. I say this as someone who studies this model professionally.

    It also can’t account for why rodents will overeat and become very obese on a cafeteria diet (human junk food), but not as obese on a high-sugar/refined carbohydrate diet or high-fat pelleted diet. Then there’s the finding that humans and rodent will eat more if food palatability is increased, even if the nutritional composition of the test diets is identical. These effects cannot be ascribed to the metabolic effects of food.

    These effects act through well-characterized interconnections between brain areas regulating reward and hedonic processing. For example, there is a major pathway between the nucleus accumbens and the lateral hypothalamus, which indirectly influences the activity of neurons in the arcuate nucleus. There is another pathway between the ventral tegmental area and the LH. The NAc and the VTA are both major canonical reward/hedonic processing centers and they are reciprocally interconnected with the hypothalamus. The lateral hypothalamus itself, one of the canonical hypothalamic “feeding centers”, is also intimately involved in reward processing– animals will compulsively stimulate themselves if you place an electrode into this region. Drugs that influence reward pathways in the right way (Rimonabant, Contrave) cause fat loss in humans, and the mechanism is thought to involve indirect effects on the hypothalamus.

    It is true that metabolic factors influence reward. For example, obese people have alterations in the brain activity of reward/hedonic pathways that I doubt are entirely attributable to pre-existing differences (although some of them are clearly pre-existing according to several lines of evidence). Many researchers see food reward as a vicious cycle: reward sensitivity increases food intake, which increases fat mass, which alters metabolism in a way that influences reward, which increases fat mass. However, the fact that reward changes over the course of fat gain does not exclude the possibility that reward was a problem to begin with. I believe the evidence suggests that it is a problem both in the initial stage of fat gain, and after significant fat has accumulated. Cheers,


    • Todd


      Thanks for your detailed and thoughtful reply! I had looked at some references regarding intrinsic hypothalamic leptin resistance, but was uncertain as to the strength of the supporting evidence. But based upon your endorsement, I’ll go back and take a closer look.

      You ask why Americans have dramatically increased their caloric intake over the last 40 years. That is indeed the key question! Unfortunately, so many variables have changed that it is difficult to say with certainty which factor or factors are most responsible. You suggest that “food presentation” radically changed in the 80s. I’m not quite sure what that means, so I’d be interested to know if you could expand upon that idea and point us to supporting evidence that food presentation suddenly changed in the 80s, and led to increased caloric intake. Here is an article showing annual consumption of high fructose corn syrup and soluble fructose in foods between 1960 and 2000: http://www.ajcn.org/content/79/4/537.long. In Figure 1, note the sharp rise in HFCS consumption in the 1980s. I’m sure that fructose is not the only factor, but combined with all the clinical and mechanistic studies in humans and animals, it does look like a key factor. You ask what caused us to eat more foods with HFCS? Well, for one thing, it barely existed as a product before 1970. Food and beverage producers started adding HFCS to a very large number of processed foods, including ketchup, bread, yogurt and foods you would never suspect are sweetened. It wasn’t really a conscious choice of Americans to start consuming HFCS — it was a decision of the big food companies who wanted to save money and improve “palatability” as they judged it.

      You are certainly right that there are many other neural processes outside the hypothalamus that influence “reward” and hedonic processing, and I hope to learn more from you, being an expert in the neurobiology of eating behavior and obesity. But don’t these other centers like the NAc, LH, VMH, and VTA ultimately feed into the ARC? My understanding is that the arcuate nucleus is the ultimate integrator of the various inputs from both other brain centers and peripheral nutrient and hormone signals. If I’m wrong about this, then I would just modify my hypothesis to a somewhat wider set of distributed neural processes. But I still think there is a relatively circumscribed part of the CNS that is in control.

      I suspect the main reason you think a purely hypothalamic is incomplete is that it does not account for the impact of sensory inputs like flavor, texture and vision on appetite regulation. And I certainly agree that flavor and other sensory inputs, particularly those that are conditioned by reinforcement, are critical to the regulation of appetite. In fact, some of my early posts are just about the sort of Pavlovian effects observed by Cabanac, Sclafini and others whose animal experiments on flavor and appetite inspired Seth Roberts to invent his Shangri-La Diet. And I’ve used similar principles to develop my own Deconditioning Diet. But if sensory cues can enhance or suppress appetite, this must occur via afferent pathways. I suspect that this may occur via sensory centers and inputs such as the tractus solitarus and vagus nerve, which ultimately provide signals that modulate the NPY/AgRP and POMC/CART neurons, or perhaps more directly the MC-4 receptor. I’m currently doing some reading about this, and would be interested in your thoughts.

      What also interests me about the hypothalamus is that it not only controls the subjective experience of appetite; it also controls the peripheral action of hormones like insulin and norepinpherine that regulate glucose and fat metabolism. In fact, it one of your recent posts, which I cite in my post, that made me aware of this “remote control override” function of the hypothalamus.

      Perhaps you will ultimately pull me closer to your own position. But what I’m still looking for in the Food Reward Hypothesis is a more mechanistic understanding that explains how the sensory attributes of food are either inherently rewarding from the start, or what they do to the brain to get that way. The theory also needs to explain why it is that foods that are rewarding to one person or one culture may not be rewarding to another. What FRH lacks, I think, is a mechanistic process model that explains what causes reward to increase and decrease over time, between individuals, and across cultures.



  14. Rahul

    I must confess this article actually brings me more confusion! I’ve been following your advices the first time a friend recommend me the site and it has literally changed my life, I’ve practiced IF in the 16-19 hrs restriction variant with a good success (till recently I didn’t knew that sugars where the big evil in diet so I’ve followed a very bad diet like eat-any-crap-food-tasty-sweet and fast, and still experience a considerably weight loss) so when I knew the potential traits of sugar I’ve cut-down its consumption to a great extent, I just allowing myself to eat grapes, apples, mandarins, sources of natural/unprocessed sugars(fructose) BUT you are saying that now even Fruits are bad? that should I only eat an anorexic apple for a day or a single grape?… ok, if that is the case I better blow my head with a gun or hang myself because I don’t think life’s is worth to live counting with nanomeric precision the amount of omega-3, acid that, triglycerides you eat, I think you are demonizing natural/unprocessed fructose present in foods and remember that nature is not as linear and same components in different combinations can have almost opposite effects, you cannot compare a fresh mango with his health benefit and say people should avoid to eat more than one mango portion just because it has fructose…. a mango is not reduced to its components and the organism will never digest a mango as it will digest all his component in a pill.
    While I think people do should avoid a soda which has like 10 teaspoons of sugar mixed in an unnatural way I don’t think if exist a natural fruit that has almost the same amount of fructose would be unhealthy and fatty to eat, is not the same.
    Also, did you know keffir? is a dairy, but a very healthy one that actually helps to loose weight, because, again, is not a linear combination of fats, ,maltose and other demonized components and is much more, russians have consumed keffir for centuries in huge amounts (amounts that people that measure till the last milligram of what they eat may be terrorized, like 1-2 liters a day) and are not obese and in fact very healthy …. please help me to solve that confusion.

    • Todd


      I’m always sorry to disappoint or confuse a loyal follower! Perhaps I did not explain myself as clearly as I could have in my post. I am definitely not advising anyone to cut fruits or other fructose-containing foods from their diet. Fruit is not bad! It contains healthful vitamins and phytonutrients and it tastes great! What I’m saying is be careful not to consume an excess. The liver can actually tolerate a fair amount of fructose and sugar, storing these as glycogen in the muscles, before the fructose becomes “too much”. Only at the point of excess does the liver start turning fructose (via citrate) into triglycerides and inflammatory fatty acids like palmitate. And only when these metabolic products become elevated do we see problems at the hypothalamus. This situation of excess is fairly typical with the Standard American Diet, which frequently involves consuming many cans of sugary soda, desserts, excess alcohol, etc.

      But if you eat fruit in moderation, and particularly if you exercise and peace IF 16-19 hours each day, then you are almost certainly avoiding this problematic accumulation of triglycerides and free fatty acids. It is almost certain, but if you have any doubt, check your levels of triglycerides and C-reactive protein (a key marker of inflammation) next time you get a checkup at the doctor’s office. Likewise, I agree that kefir, yogurts, and other fermented dairy products are probably quite healthful. The high fat content most likely not a problem for most people. Fermented dairy products appear to have a different fatty acid profile than regular milk, and studies show kefir does not cause hyperlipidemia or high cholesterol: http://www.biomedcentral.com/1472-6882/2/1

      Finally, I think you are probably right that the nutritional value of food is not just a linear combination of individual ingredients. You have to look at the whole. For example, a long chain saturated fatty acid than in isolation would result in stiff cell membranes or inflammation will often be completely harmless, or even beneficial, as part of a mixture of fatty acids that includes shorter chain saturated fatty acids and some unsaturated fatty acids.

      Hope this explanation helps, and hope to keep you as a reader!


      • Rahul

        Oh Thanks for your reply! it actually solve my concerns!
        I live in Cuba, a country with many food problems but luckily we have access to fresh and natural fruits, I even myself like to go with friends to the forest and pick mangoes, guavas, oranges, coconuts, and several other fruits just for fun, in other cases we just buy of course but always fruit is consumed at most few kilometers from where is collected. I do in the past tend to consume lots of sweets, homemade but still lot of sugar everywhere, Cuba is a world producer of sugar cane so is very easy to get (though not very refined sugar, brown) but what amaze me most is that even when I follow a disastrous diet of consuming lots of sweets, ice cream, candies, along with rice, beans, meat, salad, when I started to apply IF I still lost 10 kg and maintain weight with that crappy diet!!!! from 85 kg till 75 kg.
        Luckily I got informed about the traits that sugar did and combined a sugar free or almost free diet with IF fasting I hope to finally get rid of many of the rebel fat pounds!
        Thanks for that!

        • majkinetor

          Do you have any experience with policosanol ? I heard its used as panacea in Cuba.

        • Rahul


          No, I haven’t heard of that drug there, but acording to wikipedia:

          “Published studies have come to conflicting conclusions regarding the efficacy of policosanol in lowering LDL (i.e., “bad cholesterol”) or raising HDL (i.e., “good cholesterol”).[5][6][7] Despite a number of studies funded by the Cuban government, which produces and markets the drug,[8] independent clinical trials have found no evidence of the efficacy of policosanol.[5]

          This is very common in our government, they claim miraculous achievements and in true they are lies, our Medical System is a Huge Fail, contrary to the world spread opinion.

        • majkinetor

          We have a problem there – Cuban form of policosanol from sugar cane is not widely available in the US. Policosanol made in the US may be made from wheat germ or from beeswax. So those are different compounds which might explain the different results.

          Many people report benefit. Its even promoted in 4-Hour-Body book for weight loss.

        • majkinetor

          BTW, wikipedia has bias against “natural” supplements.


  15. David I

    Nice post, and an intriguing theory (although I think it is more like a big piece of the puzzle than a comprehensive theory).

    Two points worth mentioning, however. First, I don’t think it makes any sense at all to take studies on mice that involve hours and try to translate them to humans. If you normalize to lifespan, a mouse fasting for 16 hours is like a human fasting for more than 23 days; 48 hours is 70 days. This is one of the problems that continues to plague experiments in longevity and caloric restriction.

    Second, for those who care, the Eades (in “The 6-Week Cure for the Middle-Aged Middle”) have a more ainteresting way of sorting out visceral and subcutaneous fat than that in “Protein Power.” Stand with lower back pressed against a wall and use a ruler to measure how far your belly sticks out from the wall. Then repeat lying on the floor. If the two measurements are very similar, then your adiposity is mostly visceral. If the measurements are very different, then your adiposity is mostly subcutaneous (subcutaneous fat sags, while visceral doesn’t).

    The reclining stomach “height” is a better predictor of cardiovascular risk than waist circumference or other measures. There’s a good list of references at


    • David I

      PS Also known as Sagittal Abdominal Diameter (standing) and Supine Abdominal Height (reclining). See:




      • Todd

        Thanks for these links, David.

        I agree that mice hours and human hours may not be comparable on an absolute basis, and so can’t be taken as useful guidelines for IF timing. However, the pattern showing that TGs are high both in the fed state and long term fasting, but decline in short term fasting, is worth following up with in human studies.


        • The issue of timing; how about the CR studies on monkeys? That should be much more comparable.

  16. Al


    Thanks for your work.

    You said:

    “Thaler et al. , Schwartz et al and Benoit et al. showed that one particular long chain saturated fatty acid — palmitic acid — causes inflammation and reduces insulin sensitivity in the hypothalamus, leading to overeating and obesity.”

    A few comments in addition to what another reader mentioned about isolating palmitic acid:

    – I’m not sure what rodents fed an unnatural diet can tell us about the human diet, but it is interesting because rodents can adapt to other foods and there were differences between the subject groups of rodents.

    – those three studies all referenced another by Xiaochun Zhang, et al., where the researchers fed the rodents lard. Assuming that they did not render it themselves, could the hydrogenation been a confounder?

    – the Benoit group made their own chow. Hmmmm. I don’t think anyone here denies real whole foods, but again, it is interesting that the mix with olive oil was protective while the mix with whatever anhydrous butter is was not.

    However, you did mention that the jury was out on which natural fats are pro-inflammatory. Are you a fan of Dr. Ayers?


  17. Todd


    Ayers and his blog — “Cooling Inflammation” — are a great source of information on inflammation on diet. He has pointed out the problems with excess carbohydrate and n-6 fatty acids as inflammatory agents. I agree that most natural saturated fats are probably safe, but I’m not sure I would agree that all saturated fats without limit are harmless. I’m also not sure I would demonize all starches like potatoes and rice, as Ayers seems to, particularly if eaten in moderation.


    • Al


      I can’t speak for Dr. Ayers, but I would think that he is concerned with the inflammation caused by excess glucose at the cellular level; so yes, in moderation, because potatoes and rice do not as a substance cause inflammation, they may be ok.

      I agree about unlimited sat fat, although due to my own and some others extremely excessive intakes of sat fat in a low-carb context, it is probably not as unsafe as excessive carbohydrates and/or processed foods.

      This is a very interesting hypothesis that you have laid out here. My suspicion is that it may eventually lead back to low-grade chronic systemic inflammation. The brain may be protecting itself by storing away excess energy (like when you get sick). You need to eat more because the rest of cells still require energy. People who do not show increases in adipose tissue but present with other conditions related to metabolic dysfunction might actually have dysfunctional fat cells.

      It is also meaningful that we turn the focus back onto physiology and not Calories. I think that Dr. Guyenet might be back onto Calories, but only in the sense that food reward and hypothalamus control cause over consumption due to food choice. The key is that the body is allocating excess energy to fat stores, not because of the amount of energy you eat, but because of some dis-regulation somewhere – and this is the crux of the many debates.

      Thanks for the exchange.


  18. Michael

    by the way, about the sumo wrestlers:

    they typically eat a large high carbohydrate meal at the end of the day. without all that rice they wouldn’t get fat but at the same time if they keep their big carb load at once a day that might explain why they’re more insulin sensitive compared to the average obsese person who eats high glycemic or high fructose foods multiple times a day.

    they also typically train on an empty stomach to avoid the lack of energy that would result from the insulin spike.

  19. Rob R

    Hi Todd,

    Thanks for the summary. It helped make a lot of sense of what I had been reading about inflammation at whole health source.

    Is there an upper limit on taking anti-inflammatories? I currently take turmeric + black pepper, ginger, fish oil, cinnamon, and coconut oil daily and am wondering if I’m at risk of over doing it.

    Thank you


    • Todd


      In your list, I would consider fish oil and coconut oil as anti-inflammatory compounds, but I’d classify turmeric, black pepper, ginger and cinnamon as phytonutrients (See my post, “The case against antioxidants“, which explains that comment).

      It’s hard to put a number on a reasonable upper limit for either category. Your need for anti-inflammatories is lower if you are in great health, but it doesn’t hurt to take 1-3 tablespoons of the fish oil and coconut oil daily. The phytonutrients like pepper and ginger are classic hormetic compounds. A little is good, too much can backfire, and you can slowly build up a tolerance. On your list, turmeric (in curcumin) is one of the most effective, from what I’ve read.


      • Rob

        Thanks Todd that clears up a few things.

        I’m not megadosing anything, mostly having about 1 Tbsp of each everyday in my cooking. Maybe a bit more on the garlic and ginger sometimes. (Minus the Cinnamon, which I keep to 1 tsp at most due to toxicity concerns).

        I’ll keep up what I’m doing until I notice problems and won’t bother supplementing further with ALA or CQ10.

        As an aside. I combine black pepper + turmeric to get more blood brain barrier penetration with free curcumin. The piperine in black pepper increases curcumin bioavailability 2000% in humans. It may also increase the BDNF and MAOI potential.

  20. George


    Loved this piece! I’ve been an apple since I was 8 years old and have never, ever, ever come close to getting rid of it. Do you have any suggestions on good foods to eat in order to get rid of the intra-abdominal fat? Even if it’s just a handful, I’d really appreciate it!

    Got the coconut oil part and avoiding grains/grain fed meats, but would love a few standbys to focus on.

    Happy new year!

    • Todd


      OK, here are a few specific suggests to help pare down that apple:
      1. Add a lot more green (non-starchy) vegetables to accompany your meats & fish: broccoli, asparagus, brussels sprouts, etc. Top with butter, parmesan cheese and spices to make them tasty. Fill yourself up with veggies!
      2. Eat more eggs and more fish.
      3. Minimize bread or baked goods, and look at the labels to avoid “partially hydrogenated” fats (=trans fats)
      4. Cheese and nuts are OK, but eat modest amounts. They are easy to over-consume.
      5. Just as important as diet is adding more intense exercise to your routine. Not walking or slow treadmill, but heavy weightlifting (if you can lift more than 7 times, that’s not heavy), short sprints (until you are panting hard), or (my favorite) rock climbing. Pushing the heart and lungs to the limit will do wonders to attack the belly fat. Do it at least twice a week, and you’ll notice results within 2-3 weeks.

      Try some or all of the above and report back to let us know what works for you.



      • George

        Thank you so much! I was bouncing around a few other threads and starches were encouraged, but I’ll give your method a shot first to gauge results. Already on a paleo diet, so no problem on the breads and such… but I’m eating way more meats than I am vegetables. I’ll have to reverse that and monitor my progress..

        Re: exercise – do you mean sprint/lift/rock climb a total of 2 days a week? Or do them all separately 2 days a week (6 days total)?

        Thanks again!

        • Todd


          I think that doing intense exercise for 30-90 minutes on 2-3 different days of the week should be good enough. It’s great if you end up having energy for more than that, but be careful not to over train or tire yourself out. Hormetic stress works best when you allow sufficient time for recovery. If you are really doing things intensely, 2-3 days a week should be plenty!

          Paul Jaminet and others encourage eating a moderate amount of “safe” starches like rice or potatoes (as opposed to bread). This might be good for “maintenance mode” and for certain other functions (like avoiding dry eyes and boosting immune health), but for many people I think that starches can definitely slow weight loss.


  21. Sue

    Great post and blog all round. Found your blog a little late but glad I did!

    • Sue

      Todd, I think the safe starches can be eaten post the 2-3 intense exercise sessions you suggest without any negative effects on weight loss. It is also gives more variety to diet, perhaps better diet compliance.

  22. Tim


    Would it be accurate to simplify the leptin element of this post by saying elevated triglycerides is the reason for excess SC fat? Conversely, lowering triglycerides to normal range should consistently eliminate excessive SC fat in the long-run?

    If this is true, wouldn’t fibrates be effective appetite suppressants for the obese/very obese(high serum leptin)? Would further reducing trigs by using high-dose niacin, omega 3s and low-fructose/carb further reduce appetite/set point? Is that too strong of an assumption, based on your post?

    Although I’m very hopefully about this, it almost seems too simple: triglycerides as the cause of obesity – at least excess SC fat. It seems like that would be the type of thing that would have been discovered a long time ago.

    Stephen G. wrote the below comment. Has there been any further discussion on this point? It seems to be the core counter-point to this hypothesis.

    “The BBB permeability hypothesis is interesting, but it isn’t nearly as well developed as the hypothesis that leptin resistance intrinsic to hypothalamic neurons contributes to obesity…Triglycerides don’t just float around in the circulation, they are contained in lipoproteins, and it has never been shown that triglyceride-rich lipoproteins (VLDL and chylos) can decrease BBB permeability.”

  23. Hi Todd,

    What are your thoughts on MSG as a potential contributing factor in obesity?
    This study states that MSG intake is positively associated with weight increase and their possible mechanism is by causing leptin resistance in the hypothalamus.
    Since MSG is a flavour enhancer and an excitotoxin, I’d say it could be the link between your HH and Stephan’s FR theory.

    A question I’d have about Stephan’s “cafeteria diet” is whether they take into account food additives such as MSG when stating that “the nutritional composition of the test diets is identical”

    • Todd


      Thanks for the link and your interesting suggestion. The article provides some plausibility to the idea that MSG is obesogenic and acts via hypothalamic damage. However, as the article points out, even with higher MSG consumption in their diet, Asians have lower BMI’s than Westerners — noting further that obesity is a multi-factorial problem. So it may be fair to say that MSG is one factor involved in obesity and appetite dysregulation — but most likely only one of many factors, including a number of pro-inflammatory factors in the diet such as fructose and processed high omega-6 vegetable oils.

      To go a step further and link food reward to excitotoxins in general, we’d need to know more about the composition of high-flavor diets like that cafeteria diets cited by Stephan Guyenet. I doubt that MSG and excitoxins were explicitly tabulated in the studies he cites, but one could probably make some reasonable estimates.

      Again, I appreciate your suggestion.


  24. Glen PDQ

    Your article was extremely interesting. I was able to lose 50 lbs going from 280 down to 225 by eating very low carb and eating high protein and high fat and getting to bed earlier in the evening as I believe a proper circadian rhythm can help heal the brain. Liquid fats I included were coconut oil, grass-fed butter, and oils of olive, avocado, and macadamia.
    Severely limiting omega-6 fats is a central part of my eating habits.

  25. marcus volke

    just a comment on what the author said here –
    “In its favor, CIH can account for the close correlation between obesity and hyperinsulinemia, and the success of low carb dieting. However, it manifestly does not explain why many obese people, like Sumo wrestlers, are insulin sensitive, with normal insulin levels and no indications of diabetes, cardiovascular disease, or other signs of Metabolic Syndrome”

    Actually it can explain that. Gary taubes explicitly stated that carbohydrates improve insulin sensitivity in the fat cells, but not in the muscles cells, that is the first adaptation and it leads to obesity. The second adaptation is that fat cells eventually become insulin resistant as well as muscle cells, and then you have diabetes.

    furthermore studies confirm his assertions that hyperinsulinemia causes insulin resistance –

    Raising glucose, raises insulin, increases insulin resistance…
    Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.
    Diabetologia (2004) 47:31–39
    “Conclusion/interpretation. When the plasma insulin response to oral glucose is related to the glycaemic stimulus and severity of insulin resistance, there is a progressive decline in beta-cell function that begins in “normal” glucose tolerant individuals.”

    Barbara B. Kahn and Jeffrey S. Flier, Harvard Medical School
    The Journal of Clinical Investigation, August 2000 | Volume 106
    “Hyperinsulinemia per se can cause insulin resistance by downregulating insulin receptors and desensitizing postreceptor pathways, as was confirmed by overexpression of insulin in livers of otherwise normal transgenic mice. This transgene resulted in an age-related reduction in insulin receptor expression, glucose intolerance, and hyperlipidemia without any primary genetic defect in insulin action or secretion.”
    And again…
    Alternative Approach to Treating Diabetes Tested
    ScienceDaily (June 10, 2011)
    From; Deletion of Insulin-Degrading Enzyme Elicits Antipodal, Age-Dependent Effects on Glucose and Insulin Tolerance.
    Plos One June 2011 | Volume 6 | Issue 6
    “It’s an example of too much of a good thing [insulin] becoming bad for you…chronic hyperinsulinemia seemed to actually cause diabetes. As they aged, the mice appeared to adapt to the chronically high insulin levels, for example, by reducing the number of receptors for insulin in their tissues. These adaptations make the mice less sensitive to insulin, which is the exact cause of type 2 diabetes.”
    And again…
    Insulin: In need of some restraint? Salk Institute
    Proceedings of the National Academy of Sciences,March 07, 2007
    “the study reveals the “dark side” of high insulin production, the kind that results from over eating and obesity. “Insulin is very effective at lowering blood sugar, and promotes fat storage, preparing the animal for times when food may not be available,” he says. “But when the hormone [insulin] is produced at too high a level for too long, the body becomes insulin resistant and blood sugar and certain blood lipids gradually creep up, which can cause progressive damage to multiple organ.”

    And of course insulin resistance goes hand in hand with leptin resistance. Gary taubes’ preoccupation with insulin was a tad myopic, and apparently he did not know how it interrelated with leptin resistance.
    But his conclusions were still probably sound.

  26. Kyle

    If circulating levels of leptin are higher in females than males doesn’t that suggest females being less sensitive to leptin?

    • Todd


      While the appetite centers of female brains are more sensitive to leptin, the problem in obesity is that the leptin is not getting into the brain to signal satiety. It’s a problem of leptin resistance. As I wrote above,

      The “normal” cause of obesity involves involves leptin resistance or hypothalamic insulin resistance, whereby there is plenty of leptin or insulin circulating in the bloodstream, and the appetite-suppressing POMC neurons are functional, but not all of the hormone is reaching the receptors in the hypothalamus. The messenger is yelling, but the ears hear the message faintly. There is a barrier or impediment between messenger and receiver. The result in each case is that appetite is not getting satisfied, so there is a drive to overeat.

      Later in the article, I pointed to evidence that changes in the blood-brain barrier are associated with the leptin resistance that reduces the ability of the hypothalamus to “hear” the leptin circulating in the bloodstream. Hence, the drive to overeat and further drive up leptin that is produced in fat cells. A vicious cycle!

      In short, while female brains specifically are more sensitive to leptin, leptin resistance at the blood brain barrier results in overweight women being overall LESS sensitive to leptin.

      Hope that explains it.


      • Kyle

        Do you mean that if you gave females an intracerebroventricular leptin injection it would result in greater decrease in food intake than in males? I still think you would have to say that women are less sensitive to leptin though in that they have higher circulating levels at energy balance than men. It would be like saying someone who is hyperinsulinemic and not euglycemic is more sensitive to insulin than someone who is euinsulinemic and euglycemic.

        • Todd


          The focus of my article wasn’t about differences between male and female brains, so my main argument about obesity doesn’t depend upon whether or not the difference is real. I was citing this only as an interesting research result. Here is the link to the original article, if you are interested. I notice the work was done in rats, not humans, though it’s likely that you would see similar hormonal effects in humans:


          As I mentioned in my first reply to you, I would agree to say that women are “less sensitive” to leptin if you are looking at the NET effect, that is, the combination of the blood-brain barrier and the ultimate receptor; and that accords with the fact that they have higher circulating levels of leptin than men. But if you are looking at “sensitivity” just in the brain, then women’s brains turn down appetite in response to lower doses of leptin than do men’s brains.

          In short — I think you and I are in agreement.


  27. Brian


    I appreciate your work here very much, and I think it makes a lot of sense. Your hypothesis certainly provides a good explanation for the role the hypothalamus plays in the regulation of fat deposition and the roles triglycerides (via fructose), and palmitic acid play in hypothalamic control of appetite.

    Although craving has been alluded to in some of the discussion, I am left wondering why the obese person seems to selectively crave the very foods that are, in fact, the cause of the inability of leptin and insulin to reach the hypothalamus – what causes them to crave more of what is killing them? I suspect this is due to built-in, anti-starvation mechanisms. Unfortunately, I think that this information (the hypothalamic hypothesis), for the average obese person, is akin to research regarding the negative effects of smoking for the smoker. Most will acknowledge the soundness of the reasoning, but can’t put the information into practice because of the overwhelming drive to continue the unhealthy behavior. I am certainly not suggesting you are responsible for changing anyone’s behavior, just thinking out loud, or in type, as it were.

    • Todd


      You raise the excellent question of why food cravings are in some sense self-reinforcing. I don’t have any conclusive answer, but it does make evolutionary sense that this behavior could be advantageous in pre-industrial environments of food insecurity, for example, where consuming fructose rich late summer fruits would help to put on a little extra weight in the autumn before a food-scarce winter. In the modern world of continuous food abundance, this can lead to an evolutionary mismatch wherein the drive to overeat continues indefinitely, without the normal seasonal checks and balances.

      Once we understand the mechanisms of obesity, we can exercise conscious control by steering ourselves to eat foods that have a reduced tendency to impair the transit of appetitive hormones across the blood brain barrier. Intermittent fasting and exercise will also help to clear triglycerides and palmitate, restoring insulin and leptin sensitivity. The key here is to realize the folly of trying to restrain eating while eating foods high in fructose, sucrose and palmitate. It’s not just “calories in, calories out”, but how those calories interact with the hypothalamic control of appetite.

      More recently, I’m realizing the role that gut microflora play in obesity and appetite. What is cool is that the “good” gut microflora (Bacteroidetes) and their fermentation of fiber to short chain fatty acids alters the balance of appetitive hormones in a manner opposite to those of the “bad” microflora (Firmicutes). This linkage works through the vagus nerve, and ultimately through hypothalamic regulation of appetite:


  28. Jazz

    Hi Todd, stumbled across your site after researching leptin, appetite etc and am in heaven now reading everything I can. Thank you for sharing this information with us.

    Over the last 18 months I have lost 50kg using juice fasting, low carb, Alternate Day Fasting (JUDDD), IF (one meal a day) no sugar/gluten and any hack that I come across. I’m one who seems to do well on fasting with stringent rules because having food in “moderation” is something I can’t do. I’ve reached my goal weight and for the first time in my life people describe me as skinny, but the hunger has now pounced back like a tiger and I battle with bingeing. This weekend I was in a manic food-drunken stupor stuffing everything that I wasn’t supposed to eat including sugar, fried chicken, potatoes, chips (but not bread, cakes or nuts – somehow part of my brain was still working).

    It can’t be just lack of willpower, I’ve got that, I’ve proved it but at times I feel like I’m fighting a raging monster who constantly just wants to revert into old fat me. Sometimes I get so sick of the fight I feel like giving in but I just don’t want to feel that unhealthy again.

    One interesting thing is we are told to “eat lots of veggies”. I’ve been reading Dr Richard Bernstein’s diabetes book (I’m not a diabetic but my parents were type 2 and other family members have issues and I believe I am carb sensitive) and it’s an interesting read. What struck me was his “Chinese restaurant syndrome” – where even eating a huge quantity of veggies can create blood sugar spikes due to stretching of the stomach and the body raising insulin to compensate.

    A patient of the Dr’s had her BS raised by eating a whole head of lettuce. This could explain why even eating a large meal of low cal food can turn into a binge shortly after. The more satiety and then subsequent pain in my stomach – the hungrier I get and the more I stuff in. I guess you may have to be a binger to understand this. For instance my normal eating husband, stops when full, but I can’t. Do you think this is still just an issue of insulin sensitivity for me? That eating large meals, whatever they are, might be the trigger as it creates high insulin levels which in turn create crazy hunger for someone like myself prone to bingeing.

    I am going to adopt some of Dr B’s diet strategies and bring my carb intake even lower (no fruit) and omit some veggies (onions which I love) and eat smaller meals in an attempt to control the insulin and see if this helps. I am also going to adopt your strategies (ie. continue with IF) I do regular walking/cycling but I will need to stress myself more (any suggestions for us more mature females, get more regular sleep and cold showers, well I will work on those.

    Todd, is there is anything else you can recommend to kill this bingeing, raging monster within I would be most grateful.

    • Todd

      Hi Jazz,

      Losing 50 kg (110 lbs) in 18 months is no mean feat – kudos for such an accomplishment. Ultra low carb, ketogenic diets and IF are great approaches to weight loss, as your own experience shows. However, I am concerned about the fact that you cannot deviate from a very strict diet without bingeing. It’s important to get to a point where food is not the enemy, and that you are not so carb sensitive. It sounds to me like you are both leptin and insulin resistant. Your brain cannot “hear” the insulin that is produced in response to carbs or a big protein meal, leading to intense, nearly irresistible cravings. Only by bingeing are you able to raise your insulin levels high enough to finally reach your hypothalamus and shut off the hunger signaling.

      Merely keeping your your carb intake low won’t reverse your insulin resistance. You need to take active steps to do this. As a mature female, regular exercise — including weight lifting or other intense workouts — is a big help. Dr. Bernstein has a number of chapters in his book on the importance of exercising “until exhaustion” using techniques like the inverted pyramid. (See my Fitness page on this).

      Try not to be so fearful of fruits and vegetables, particularly those that have relatively low sugar and high levels of insoluble fiber, like avocados, blueberries, strawberries, asparagus, broccoli and the like. (Lettuce is relatively weak in this regard). This type of fiber helps to shift your intestinal microflora over to the “good” bacteria that play a key role in reversing insulin resistance. It takes 2-4 weeks for this effect to kick in.

      You should also consider the psychological side of your insulin resistance. I’ve developed a “Deconditioning Diet” (See my Diet page) with recommendations on how to break the psychological connection between food and hypoglycemic cravings. It takes the diametric opposite approach of avoiding trigger foods by using cue exposure therapy to extinguish those cravings.

      Some people advise the use of insulin sensitizing supplements like zinc, chromium, 5-HTP, amino acids and gymnemna sylvestre to control cravings. These may help in the short term, but I’m not sure they provide a long term solution. See the thread “Sugardude’s Diet Puzzle” on my Forum for the odyssey of someone who has made attempts using supplements to stop bingeing.

      Good luck,


      • Jazz

        Wow thanks Todd for your insightful and scientific response. Thank you for the links. I have adopted your strategies and what has been most helpful is your advice to not give in to cravings as they hit as it reinforces them.

        I have already had success with your deconditioning. It was an errant organic white chocolate licorice ball in my car left from a previous binge. I picked it up and sniffed it for a few mins and and then threw it out. The old me would have gobbled it and then thought hell stuff it and bought 2 packs to gorge on followed by a manic day of gluttony culminating in misery and self-loathing.

        In some ways I have already practised deconditioning whilst losing weight I still had to prepare food for my family. When I came across cakes, crisps, biscuits, sweets I would open the packet and just breathe in deeply and savour the aromas and be satisfied. Somehow along my weight loss “journey” I stopped doing this and became afraid of the junk – out of sight out of mind so to speak. So I am starting to do this again.

        Yes I do believe I still have leptin and insulin resistant issues not giving my brain the correct signals, and I wonder if this is just my particular genetics with having both parents developing late onset type 2 diabetes as well as numerous siblings and cousins with blood sugar issues (most at normal weights, I mean there is no-one in my family morbidly obese. Incidentally my father developed diabetes after commencing statins…coincidence??).

        Anyway what do you think of using Metformin to help with my insulin issues in an attempt to extinguish the binges? I certainly don’t want to use medications or be on them for the rest of my life but do you think in light of my family history this might be an option for me? Everything I read about this medication seems that it’s not a bad type of drug and may even have some positive aspects; but do I want to be on it for the rest of my life? Yes if it can give me control over the binging which can’t be good for my health in any case.

        Lastly there is one strategy I’m employing before I get desperate enough for the above idea. I respond well to discipline and rules so I have been experimenting as from this week. I am eating only one meal in the afternoon and have two 40 hour fasts under my belt as of the end of today ie basically one meal a day (snacking on CO if desperate)and omitting that evening meal once a week. This has brought me in line already, no binging and some water weight loss so I feel and look better in my clothes. The long fasts pull me in line like nothing else and free me from food obsessions.

        In fact Todd I averted a binge yesterday. I woke up hungry and stupidly made an enormous batch of cocoa crack with CO and blueberries, followed by three fried eggs. High fat food but it still created a hunger and a binge “stuff it” remorseful mindset of eating too many calories too early in the day (the longer I avoid food during the day the better for me). I quickly thought I need some damage control here and decided to start a 40 hour fast that was scheduled for later in the week. This is a huge victory as I have never been able to stop a potential binge in the past. Can I live like this? I don’t know, my new IF experiment is in the early stages and I will have to see if this gets easier and if it’s a way of life I could live with. I don’t restrict what I eat in the evenings but the fasting seems to give me some kind of appetite control and I still avoid high reward trigger foods i.e nuts, sugar, starch. Certainly a better prospect than calorie counting and three small meals daily that will only make me obsess over food all day.

        Thank you again Todd – for your generosity in sharing your wealth of knowledge. Your ideas have certainly made an impact in the short time I have applied them.

        • Todd

          I’m not an expert on Metformin, but from what I’ve read it is relatively benign and probably helpful, at least as a “transitional” solution. However, there are still some risks, e.g. lactic acidosis, and some claim that long term use may be counterproductive:

          My suggestion is: try it short term, but consider diet and exercise as your long term solution

          Since you love routine and rules, then that’s great — go with what works for you. My only concern is that such rigidity can leave you vulnerable to even a single deviation. That is why I like the idea of deconditioning — it extinguishes the stimulus-response connection, so you no longer have to always be on your guard.

          Best wishes,


  29. I notice your seven year figure. I read elsewhere that fat cells live for 7 years. A fellow who is experimenting with adipotide said that when you diet, the fat cells give up their fat, but stay alive. And when they are empty they continually dump cortisol and other hormonal “cries” for more food. So it takes 7 years of willpower to consolidate your fat loss. Just the thought makes me quail. I will look into the deconditioning too; I’ve had the same problem. So, 3 and 1/2 years in, the willpower required should drop to one half of what it takes in the first year.

    I’ve been reading the writings of Billy Craig, and it is an interesting contrast to what I read here. He is getting amazing results.

    • Todd

      I’m having trouble finding the reference to seven years. Can you point me to the mention?

  30. Jazz

    Thanks Todd, I might bring up metformin with my doc, but as we know he knowledge of nutrition is what he learnt at med school. You are absolutely correct Todd – the rigidity will get to me in the end with one deviation and it will be an almighty binge of everything I have “deprived” myself for the rest of the day. I believe deconditioning is perhaps the best way to go but I don’t understand how to apply it for binging.

    For instance, if I get a sudden craving for a trigger food then I know I can’t give into it and then at a later stage I expose myself to that food via deconditioning; I understand that and it works very well.

    However this is my scenario – say I have IF’d all day, feel great, my hunger is healthy and normal; I eat my steak and vegetables and I’m full, but I keep eating more veggies and feel full but unsatisfied and then something clicks and it becomes a runaway train syndrome. I can be completely full to the point of feeling sick and I’ll still want to keep eating. It’s more of a self-soothing hand-to-mouth-to-brain need. That’s the a point when it’s hard to stop once the brain has been triggered. I would keep going and going for no reason…even if my gut is stretched and full. Then it’s a manic drive to the shop and getting packets of all my trigger foods to stuff down; so not keeping that stuff in the house doesn’t help. How do I incorporate deconditioning in this regard to stop situation getting worse or to bite it in it’s tracks. Because there is a point of no return where nothing will help; no distraction i.e bath, calling a friend, going for a walk at this “stuff it” point. If I can apply deconditioning in this regard this would be helpful. It’s the ACT of eating that seems to trigger it, regardless of what I eat, so it’s easier to fast than eat. If I can crack this then most of my problems would be solved.

    I’m not alone or unique in this Todd, many many are in this position judging by posts and forums I come across. I have overeaten in my obese days for sure, but this is a new problem I have only come across since losing most of my fat.

    • Todd


      Thanks for supplying additional detail. Of particular note is the fact that you binge even while feeling full, with a stretched gut. And that your bingeing is driven large by a need for “self-soothing”.

      This link describes precisely those two aspects of your binge eating:

      The link points out that this type of eating to “sooth” is often associated with a deficit of serotonin (the soothing neurotransmitter) and depression. Would you say you have some degree of depression? That may be a reason to look deeper than mere biology. Therapy can help. I don’t advocate antidepressants, except in extreme cases, because they can have adverse effects. You might also consider cold showers — many have reported to me that this caused a rapid lifting of depression and a sustained sense of calm and joy. Intense exercise also helps. Both of these take several weeks to work. Also consider more social interaction, particular of the kind where you help others less fortunate or capable. It’s a great and proven antidepressant. (I must admit that whenever my blog articles help someone, it cheers me!).

      I’m still concerned about the clash between your binge eating and your rigid rules about avoidance and periodic fasting. IF is great for many people, but I’m not sure it is such a good idea for binge eaters. The link above suggests that moderate eating, not avoiding, is beneficial.

      But how do to that without triggering a binge? Here is an idea. Have you tried eating small amounts of your trigger foods at times when you (a) are satiated and not hungry at all; and (b) are in a good mood and unstressed? Doing so will help reinforce the idea of eating those foods without the factors that typically foreshadow a binge. Eat those foods ONLY when you are happy and calm. Eat ahead of any “storms” when everything is smooth sailing. NEVER eat them with stressed. The key here is to think like a Pavlovian and reinforce the behaviors you want.

      Jazz, these are only ideas. I’m not a therapist, only an idea guy. The point of my blog is to give you some ideas to run with. You may be strong enough to test them yourself, but don’t deny yourself professional help if you find this to be a burden too far.

      Good luck! And by the way — thanks for your contributions to the discussion. Every new situation helps us to refine our thinking.


      • Jazz

        Thanks Todd. I know this goes against your recommendations but I ended up on Wellbutrin due to depression/BED; I’ve had depression for years but the BED is recent. I think it’s effect on depression is subtle; it doesn’t numb nor does it give the bouncing drive/energy I have heard about. However the biggest effect has been on the binging. I still get the urge to binge and I semi-binge but with far less junky food, less guilt/self-hate at the end and I’m able to bounce back on track. I’m able to resist my trigger foods and I’m having some appetite suppresion. Ok I know this isn’t an answer and I will have to come off it at some stage, but it was doing my head in, I had to do something. I’m hoping I can use this time to work on this monster in the meantime using the cognitive and behavioural therapies that I know. Do you think CS/IF whilst taking WB would be futile? I do like your idea of eating trigger foods whilst happy – I have only eaten them during the frenzies – but do you think eating them when happy or satisfied with other food might give them reward status? Thanks in advance Todd. Again your site is such a breath of fresh air and grounding/stability in the sometimes confusing and contradictory nature of health and nutrition.

        • Todd

          Hi Jazz,

          I’m not sure what “BED” stands for — perhaps you can explain

          I’m not against the use of medication as a short term strategy, particularly since makes your situation tolerable. But you and I know it is not a good long term strategy. The key question is: how to reduce your dependence on Wellbutrin?

          This is something you’ll have to work with your doctor to determine.

          Here is my advice:

          1. Before you start cutting back on Wellbutrin, find alternative ways to overcome depression and the urge to binge. This can certainly include cognitive therapy, but it should also include a behavioral component. For example, people who want to overcome phobias or anxiety benefit from an approach that involves both cognitive therapy and gradually increased exposure. For more about this, see the guest post on this blog, “Conquer your fears“.

          2. My Deconditioning Diet is essentially the application of exposure therapy to the control of cravings. It’s counterintuitive, but it has proven effective as a way to overcome addictions and — most importantly — avoid relapse. I’ve written about this in my post, “Overcoming Addictions“.

          3. Consider another approach to overcoming depression and the urge to binge: the active pursuit of discomfort. The best forms of discomfort are those that build tolerance. My favorites are: intense exercise and cold showers. They may sound horrible, sitting where you are today. But these work! I get many private communications from those who report that cold showers and intense exercise caused their depression or addictions to disappear, and fairly quickly. Read “Cold showers

          4. With your doctor’s support, work out a plan for gradually tapering off the Wellbutrin. The key word here is gradual. The biggest mistake that people make in trying to change behavior is going too quickly — because too rapid change does not allow time for adaptation and can provoke a counter-reaction or relapse.

          Let me know if this makes sense to you.


  31. Jazz

    Thank you for your comments and BED is (Binge Eating Disorder) – it mostly originates after restrictive dieting. Think of it like Bulimia but without the purging. I do 1-2 hours exercise each day, mostly walking/hiking/cycling out in the fresh air – no gym – love it can’t get by a day without it. I know I must do weights but I loathe it..find it so boring… wish I could get addicted to it but I just can’t. I rather do weight bearing exercises such as push ups, dips but I don’t know how effective they are.

    Todd, most of my trigger foods are in shops i.e licorice and one particular chocolate. Apple, oranges and pears as well; I know fruit is healthy but many a binge started after craving and giving in to an innocent apple. My problem is obviously sugar. Should I just go to a supermarket and hold the packet and look at them; or should I buy them and take them home and smell, touch? Oh that would be painful. Todd I so wish I had control, just to eat a few pieces of these foods after a meal and be satisified and happy; but I know this will open the door to excess and binging.

    The only issue I have with CS is women who have reported (on a forum I frequent) that their thigh and stomach fat increased after this therapy. This is women who sat in baths or put ice packs on fatty areas so perhaps a CS is a different story, although I did read in one of your reader comments a male who felt flabbier after CS.

  32. Jazz

    I just wanted to add that I am lean now. I’m at a weight I’m happy with. My goal is maintenance, cementing this new weight as my setpoint, dealing with rebound hunger and my body’s push to get back to my old fatty self and not gaining the weight back..ever… I recall the guy who posted about getting flabbier after CS thought that being leaner might make a difference in outcomes.

    • Todd


      Thanks for the clarifications. Since you are reasonably lean as the result of restrictive dieting, it seems like your Binge Eating Disorder may be a reaction to your recent weight loss, perhaps compounded by some psychology. Some believe that the body has a “set point” and that sudden or dramatic weight loss will inevitably be followed by rebound. I’m not one of those people — I think that there is no genetically determined “set point”. That said, it doesn’t mean it is easy to maintain your weight loss. The hypothalamus will tend to fight back (as the above article makes clear) unless the leptin and insulin signaling can get through.

      One key to proper leptin and hormone signaling is to eat a non-inflammatory diet, to resensitize and restore hypothalamic sensitivity. I’ve already commented on how intense exercise (not just mild aerobics but anaerobic spurts) and cold showers can help. But your comment about trigger foods: licorice, a specific chocolate, specific fruits — raises another point: The hypothalamus gets strong input from the amygdala, the part of the ancient limbic system that responds strongly to emotional conditioning and meaning. The amygdala surrounds the hypothalamus in the center of the brain and feeds it a constant stream of signals. It can override even normal nutrient signaling and cause you to binge even when you aren’t hungry. It’s the part of the brain that Pavlov was concerned with in his studies of conditioning. Notice how specific your triggers are! Substitute foods won’t lead to bingeing. Trying to fill up on “non trigger” foods will not extinguish your bingeing.

      One long term participant on my site, who goes by the name “Sugardude” has a severe sugar addiction and binge eating disorder. He has tried all kinds of supplements, including amino acids, gymnema sylvestre, etc. to extinguish his sugar cravings. Everything works for a while…then he relapses. So I’m not convinced this type of problem can be addressed by nutritional correction alone. Read his post, it’s instructive:


      My personal view is that you are a great candidate for exposure therapy. The best type is so-called Exposure with Response Prevention (ERP). While best carried out with professional support, ideally as part of Cognitive Behavioral Therapy. But I also think a determined individual can make this work on their own. ERP works to address very specific food addictions and binge behaviors. Here are a few links.


      As I detailed in my post on Overcoming Addictions, the success of this approach rests on a number of well studied factors, including realistic exposure, variety of contexts, and frequency of exposure. Another success factor is developing an alternate response to the trigger or craving, and planning the response in advance. The alternate response must provide pleasure!

      ERP has been shown to be effective in completely extinquishing problem behaviors. It’s not a quick fix. But it works.

      At the end of the day your can’t fool your hypothalamus. It is in control of your eating, like it or not. If you combine hormetic practices (non-inflammatory diet, intense exercise, cold showers) to generally resenstize your hypothalamus, with specific exposure training to rewire your amygdala so that it stops harassing your hypothalamus by responding to emotional triggers — you have an excellent chance of renormalizing your appetite. Trying to exert sheer “willpower” to control your eating without understanding the power of your hypothalamus is a fool’s errand that can at best work in the short term.

      Good luck,


      • Jazz

        WOW thank you; I’m speechless. You have explained it as nobody else can. Now I need time to ingest all this information. Thank you so much; I’m practically in tears; thank you for understanding and helping xx

      • Soderblum

        I just want to add my gratitude. With a lifetime of overweight/borderline obesity behind me, it’s been quite a task to get eating behaviors under control (IF is helping enormously in a way that LC alone could never do). Understanding the concepts you outline–the pleasure deficit, reshaping brain receptors, the power of conditioning and emotional re-shaping–has been so critical to develop self-compassion and forgiveness. And without that it’s easy to be discouraged, which leads nowhere good. Many, many thanks!

        • Todd

          That’s nice to hear, Soderblum. Can you say more about the specifics of your weight loss experience, including your current pattern of eating and how it works for you?

  33. Tim

    Not sure where this would be most appropriate to post…

    Todd – when you get a moment, I’d like to get your take on the following TED talk:


    It is a talk on how anti-angiogenic drugs/foods can starve developing cancer cells of blood required to grow, which seems pretty compelling.

    At 16:30 he also discusses how anti-angiogenic foods/drugs also has to potential to reduce as fat without altering calorie intake, as shown in a mice study.

    A couple questions:

    What do you think about this as it relates to obesity?

    Wouldn’t anti-angiogenic drugs/foods increase the potential to develop the conditions that require angiogenesis (as shown on the right slide of the slide at 3:05)?

    • Todd


      I’d seen William Li’s TED talk before and I really like his idea of angiogenesis as a naturally regulated process, with imbalanced angiogenesis as a marker of many diseases. In particular, he is right to highlight excess angiogenesis as a trigger and accelerator that ignites incipient “dormant” cancers, allowing them to grow and become metastatic – and also to feed the growth of adipocytes, driving obesity.

      However, angiogenesis in itself is not a bad thing. As Li acknowledges, it involves a natural balance. As you point out in your comment, it’s actually required for a number of processes such as wound healing, hair growth and erectile function. We want natural balance of angiogenic balance, not total shutdown of angiogenesis. Thus, drugs that strongly inhibit angiogenesis should be used with extreme caution — only in dire situations and not prophylatically.

      However, I wouldn’t worry too much that the “anti-angiogenic foods” he cites (green tea, parsely, grapes, tomatoes/lycopene, turmeric) will shift the balance to excessive inhibition of angiogenesis. Foods eaten in diverse combinations generally incorporate a broad range of modulators that include a balance of inhibitors and promoters. So they may usefully inhibit excess angiogenesis, without shutting down helpful angiogenesis.

      That said, I think that angiogenesis is not the main lever in controlling either cancer or adiposity. The bigger level is excess basal insulin and blood glucose. Both cancer and fat thrive on high blood insulin and glucose levers, so intermittent fasting is my preferred anti-cancer and anti-obesity strategy. Secondarily, the benefits many of the compounds that Li cites for their anti-angiogenesis can be equally well accounted for by alternative mechanisms, including their hormetic effects on upregulation of endogenous Phase II antioxidant enzymes.


      • Tim

        Thanks, Todd. I appreciate the insights.

  34. Fructose increases palmitic acid production, but palmitic acid is a saturated, not PU, fatty acid. Not sure how bringing a saturated fatty acid into your paradigm strengthens your argument. Thus, palmitic acid would have no effect on insulin resistance.


    • Todd

      Indeed, in the above post I acknowledge that palmitic acid is a saturated fatty acid, and is implicated in the genesis of insulin resistance:

      “Certain fatty acids – trans fats, certain long-chain saturated fatty acids, and omega-6 unsaturated fatty acids — produce an inflammatory response in insulin receptors that blunts insulin sensitivity.”

      So I don’t see any contraction with the thesis argued in my post. Peat’s point regarding the role of palmitic acid in cortisol regulation seems to me to be a separate issue.


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